HRP20040151A2 - Alkyne-aryl phosphodiesterase-4 inhibitors - Google Patents
Alkyne-aryl phosphodiesterase-4 inhibitors Download PDFInfo
- Publication number
- HRP20040151A2 HRP20040151A2 HR20040151A HRP20040151A HRP20040151A2 HR P20040151 A2 HRP20040151 A2 HR P20040151A2 HR 20040151 A HR20040151 A HR 20040151A HR P20040151 A HRP20040151 A HR P20040151A HR P20040151 A2 HRP20040151 A2 HR P20040151A2
- Authority
- HR
- Croatia
- Prior art keywords
- 6alkyl
- phenyl
- dihydro
- carboxamide
- naphthyridin
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 144
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- 229910052736 halogen Inorganic materials 0.000 claims description 88
- -1 N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide Chemical compound 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 72
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Abstract
Spojevi prikazani formulom (I):ili njihove farmaceutski prihvatljive soli, su inhibitori fosfodiesteraze- 4, korisni u liječenju astme i upala.The compounds represented by formula (I): or pharmaceutically acceptable salts thereof, are phosphodiesterase-4 inhibitors, useful in the treatment of asthma and inflammation.
Description
Područje izuma Field of invention
Predmetni izum odnosi se na spojeve koji su alkin-aril supstituirani 1,8-naftiridin-4(1H)-oni. Posebno, ovaj izum odnosi se na fenil supstituirane 1,8-naftiridin-4(1H)-on, koji su inhibitori fosfodiesteraze-4, gdje je fenil grupa na 1-poziciji i sadržava 2-alkin supstituent grupu, nadalje opcionalno supstituiranu. The present invention relates to compounds which are alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones. In particular, this invention relates to phenyl substituted 1,8-naphthyridin-4(1H)-one, which are phosphodiesterase-4 inhibitors, where the phenyl group is at the 1-position and contains a 2-alkyne substituent group, further optionally substituted.
Pozadina izuma Background of the invention
Hormoni su spojevi koji raznoliko djeluju na staničnu aktivnost. Na mnogo načina, hormoni djeluju kao glasnici koji izazivaju specifične stanične odgovore i aktivnosti. Mnoga djelovanja izazvana hormonima, međutim, nisu uzrokovana djelovanjem samo hormona. Umjesto toga, hormon se prvo vezuje na receptor, izazivajući time otpuštanje ljekovitog spoja, koji djeluje na staničnu aktivnost. U ovom scenariju, hormon je poznat kao prvi glasnik, dok se drugi spoj naziva drugi glasnik. Ciklički adenozin monofosfat (adenozni 3',5'-ciklički monofosfat, "cAMP" ili "ciklički AMP") poznat je kao drugi glasnik za hormone, uključujući epinefiin, glukagon, kalcitonin, kortikotrofin, lipotropin, luteinizirajući hormon, norepinefrin, paratiroidni hormon, tiroid-stimulirajući hormon, i vazopresin. Stoga, cAMP posreduje stanične odgovore na hormone. Ciklički AMP također posreduje stanične odgovore na razne neurotransmitere. Hormones are compounds that have a diverse effect on cellular activity. In many ways, hormones act as messengers that elicit specific cellular responses and activities. Many hormone-induced actions, however, are not caused by the action of hormones alone. Instead, the hormone first binds to a receptor, causing the release of a medicinal compound, which affects cellular activity. In this scenario, the hormone is known as the first messenger, while the other compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3',5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a second messenger for hormones, including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Therefore, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Fosfodiesteraze ("PDE") su familija enzima, koji metaboliziraju 3', 5' cikličke nukleotide na 5' nukleozid monofosfat, time dovršavajući aktivnost cAMP kao drugog glasnika. Posebna fosfodiesteraza, fosfodiesteraza-4 ('TDE4")., također poznata kao "PDE-IV"), koja je cAMP specifična, tipa IV PDE, s visokim afinitetom, pobuđuje interes kao potencijama meta za razvoj novih anti-astmatičkih i anti-inflamatornih spojeva. PDE4 postoji kao najmanje četiri izoenzima, od kojih je svaki enkodiran drugim genom. Svaki od četiri poznata PDE4 genska produkta, vjeruje se, igra različitu ulogu u alergijskim i/ili inflamatornim odgovorima. Phosphodiesterases ("PDEs") are a family of enzymes that metabolize 3', 5' cyclic nucleotides to 5' nucleoside monophosphate, thereby completing cAMP's second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 ('TDE4'), also known as "PDE-IV"), which is a cAMP-specific, high-affinity type IV PDE, is attracting interest as potential targets for the development of new anti-asthmatic and anti- inflammatory compounds. PDE4 exists as at least four isoenzymes, each encoded by a different gene. Each of the four known PDE4 gene products is believed to play a different role in allergic and/or inflammatory responses.
Stoga, se vjeruje da inhibicija PDE4, naročito specifičnih PDE4 izoformi, koje proizvode štetne odgovore, može povoljno djelovati na alergije i inflamatorne simptome. Bilo bi poželjno dati nove spojeve i pripravke koji inhibiraju PDE4 aktivnost. Therefore, it is believed that inhibition of PDE4, especially specific PDE4 isoforms that produce adverse responses, may have a beneficial effect on allergy and inflammatory symptoms. It would be desirable to provide new compounds and compositions that inhibit PDE4 activity.
Veliki problem u korištenju PDE4 inhibitora jest nuspojava mučnina povraćanje koja je primijećena za nekoliko kandidata spojeva, kako je opisano u C.Burnouf i dr., ("Burnouf'), Ann. Rep. In Med. Chem,, 33:91-109(1998). B.Hughes i dr.,Br. J.Pharmacol, 118:1183-1191(1996); MJ.Perry i dr., Cellular Biochem. Biophys., 29:113-132(1998); S.B.Christensen i dr.,J.Med Chem., 41:821-835(1998); i Burnouf opisuju široke varijacije ozbiljnosti nepoželjnih nuspojava koju pokazuju razni spojevi. Kako je opisano u MD.Houslav i dr., Adv. In Pharmacol., 44:225-342(1998) i D.Spina i dr., Adv. In Pharmacol., 44:33-89(1998), postoji veliki interes i istraživanje terapijskih PDE4 inhibitora. A major problem in the use of PDE4 inhibitors is the side effect of nausea and vomiting that has been observed for several candidate compounds, as described in C. Burnouf et al., ("Burnouf'), Ann. Rep. In Med. Chem,, 33:91-109 (1998). B. Hughes et al., Br J. Pharmacol, 118:1183-1191(1996); MJ. Perry et al., Cellular Biochem. Biophys., 29:113-132(1998); S. B. Christensen et al., J. Med Chem., 41:821-835(1998); and Burnouf describe wide variations in the severity of adverse side effects exhibited by various compounds. As described in MD. Houslav et al., Adv. In Pharmacol., 44 :225-342(1998) and D. Spina et al., Adv. In Pharmacol., 44:33-89(1998), there is great interest and research into therapeutic PDE4 inhibitors.
Međunarodna Patentna Prijava WO9422852 opisuje kvinoline kao PDE4 inhibitore. Međunarodna Patentna Prijava WO9907704 opisuje l-aril-1,8-naftiliđin-4-on derivat kao PDE4 inhibitore. International Patent Application WO9422852 describes quinolines as PDE4 inhibitors. International Patent Application WO9907704 describes l-aryl-1,8-naphthylidin-4-one derivatives as PDE4 inhibitors.
A.H.Cook, i dr.,J.Chem. Soc., 413-417(1943) opisuje gama-piridilkvinolin. Drugi kvinolin spojevi su opisani u Kei Manabe i dr., J.Org. Chem., 58(2):6692-6700(1993); Kei Manabe i dr, J.Am. Chem. Soc., 115(12):5324-5325(1993); i Kei Manabe i dr., J.Am. Chem. Soc., 114(17):6940-6941(1992). A.H. Cook, et al., J.Chem. Soc., 413-417 (1943) describes gamma-pyridylquinoline. Other quinoline compounds are described in Kei Manabe et al., J.Org. Chem., 58(2):6692-6700(1993); Kei Manabe et al., J.Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J. Am. Chem. Soc., 114(17):6940-6941(1992).
Spojevi koji sadržavaju sisteme prstenova opisuju razni istraživači kao djelotvorne za razne terapije i uporabe. Na primjer, Međunarodna Patentna Prijava Br. WO 98/25883 opisuje ketobenzamid kao inhibitore, Europska Patentna Prijava Br. EP 811610 i U.S. Patent Br. 5,679,712, 5,693,672 i 5,747,541 opisuju supstituirane benzoilguanidine blokatore natrijevih kanala, U.S. Patent Br. 5,736,297 opisuje prstenaste sisteme korisne kao fotosenzitivne sastave. Compounds containing ring systems have been described by various researchers as effective for a variety of therapies and uses. For example, International Patent Application No. WO 98/25883 describes ketobenzamide as inhibitors, European Patent Application No. EP 811610 and U.S. Pat. Patent No. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Pat. Patent No. 5,736,297 describes ring systems useful as photosensitive compositions.
U.S. Patent Br. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, i Međunarodna Patentna Prijava WO 95/35283 opisuju PDE4 inhibitore koji su tri-supstituirani aril ili heteroaril fenil derivati. U.S. Patent Br. 5,580,888 opisuje PDE4 inhibitore koji sustiril derivati. U.S. Patent Br. 5,550,137 opisuje PDE4 inhibitore koji su fenilaminokarbonil derivati. U.S. Patent Br. 5,340,827 opisuje PDE4 inhibitore koji su fenilkarboksamid spojevi, U.S. Patent Br. 5,780,478 opisuje PDE4 inhibitore, koji su tetra-supstituirani fenil derivati. Međunarodna Patentna Prijava WO 96/00215 opisuje supstituirane oksim derivate korisne kao PDE4 inhibitore. U.S. Patent Br. 5,633,257 opisuješ PDE4 inhibitore koji su ciklofalkil i alkenil)fenil-alkenil (arii i heteroaril) spojevi. LOUSE. Patent No. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, i Međunarodna Patentna Prijava WO 95/35283 opisuju PDE4 inhibitore koji su tri-supstituirani aril ili heteroaril fenil derivati. LOUSE. Patent No. 5,580,888 discloses PDE4 inhibitors containing derivatives. LOUSE. Patent No. 5,550,137 describes PDE4 inhibitors which are phenylaminocarbonyl derivatives. LOUSE. Patent No. 5,340,827 describes PDE4 inhibitors which are phenylcarboxamide compounds, U.S. Pat. Patent No. 5,780,478 describes PDE4 inhibitors, which are tetra-substituted phenyl derivatives. International Patent Application WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. LOUSE. Patent No. 5,633,257 describes PDE4 inhibitors that are cycloalkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
Međutim, ostaje potreba za novim spojevima i pripravama, koji terapijski inhibiraju PDE4 uz minimalne nuspojave. However, there remains a need for new compounds and preparations that therapeutically inhibit PDE4 with minimal side effects.
Sažetak izuma Summary of the invention
Predmetni izum odnosi se na alkin-aril supstituirani 1,8-naftiridin-4(1H)-on prikazan formulom (I): The present invention relates to alkyne-aryl substituted 1,8-naphthyridin-4(1H)-one represented by formula (I):
[image] [image]
ili njegovim farmaceutski prihvatljivim solima, koji su inhibitori fosfodiesteraze-4. or its pharmaceutically acceptable salts, which are phosphodiesterase-4 inhibitors.
Ovaj izum također daje farmaceutske pripravke koji sadržavaju djelotvornu količinu novog alkin-aril supstituiranog 1,8-naftiridin-4(1H)-ona i farmaceutski prihvatljivog nosača. Ovaj izum nadalje daje metodu liječenja sisavaca, na primjer, i) plućnih poremećaja kao što su astma, kronični bronhitis, kronična opstruktivna plućna bolest (COPD), sindrom respiratornog poremećaja kod odraslih, sindrom respiratornog poremećaja kod djece, kašalj, kronična opstruktivna plućna bolest kod životinja, sindrom respiratornog poremećaja kod odraslih, i sindrom respiratornog poremećaja kod djece, ii) gastrointestinalnih poremećaja kao što su ulcerativni kolitis, Crohn-ova bolest, i hipersekrecija želučane kiseline, iii) infektivnih bolesti kao što su bakterijski, gljivično ili virusno izazvane sepse ili septički šok, endotoksički šok (i srodna stanja kao što su laminitis i grčevi kod konja), te septički šok, iv) neuroloških poremećaja kao što su traume leđne moždine, povrede glave, neurogene upale, bolovi, i reperfuzijske povrede mozga, v) upalnih poremećaja kao što su psorij atrij ski artritis, reumatski artritis, ankilozni spondilitis, osteoartritis, upala i citokin-posredovana kronična degeneracija tkiva, vi) alergijskih poremećaja kao što su alergijski rhinitis, alergijski konjuktivitis, i eozinofilni granulom, vii) psihijatrijskih poremećaja kao Što su depresija, oštećenje memorije, i monopolarna depresija, viii) neurodegenerativnih poremećaja kao što su Parkinson-ova bolest, Alzheimer-ova bolest, akutna i kronična multipla skleroza, ix) dermatoloških poremećaja kao što su psorijaza i druge benigne ili maligne proliferativne kožne bolesti, atopički dermatitis, i urticaria, x) onkološke bolesti kao što su rak, rast tumora i kancerogena invazija normahianog tkiva, xi) metaboličkih poremećaja kao što su diabetes insipidus, xii) koštanih poremećaja kao što su osteoporoza, xiii) kardiovaskularnih poremećaja kao što su arterialna restenoza, arteroskleroza, reperfuzijske povreda miokarda, i xiv) drugih poremećaja, kao što su kronični glomerulonefritis, vernalni konjuktivitis, odbacivanje transplantata i implantata, i kaheksija - bolesti koji su podložne poboljšanju inhibicijom PDE4 izoenzima i rezultirajućih povišenih nivoa cAMP -davanjem djelotvorne količine novog alkin-aril supstituiranog l,8-naftiridin-4(1H)-on-a ili prekursorskog spoja, koji formira in vivo novi alkin-aril supstituirani 1,8-naftiridin-4(1H)-on, koji je inhibitor fosfodiesteraze-4. The present invention also provides pharmaceutical compositions comprising an effective amount of a novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-one and a pharmaceutically acceptable carrier. The present invention further provides a method of treating mammals, for example, i) pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, pediatric respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, respiratory distress syndrome in adults, and respiratory distress syndrome in children, ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and spasms in horses), and septic shock, iv) neurological disorders such as spinal cord trauma, head injuries, neurogenic inflammation, pain, and brain reperfusion injuries, v) inflammatory disorders such as psoriatic arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated ana chronic tissue degeneration, vi) allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissue , xi) metabolic disorders such as diabetes insipidus, xii) bone disorders such as osteoporosis, xiii) cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and xiv) other disorders, such as chronic glomerulonephritis, vernal conjunctivitis , rejection of transplants and implants, and cachexia - diseases that are subject to pain by inhibiting the PDE4 isoenzyme and the resulting elevated cAMP levels - by administering an effective amount of a new alkyne-aryl substituted 1,8-naphthyridin-4(1H)-one or precursor compound, which forms in vivo a new alkyne-aryl substituted 1,8-naphthyridine -4(1H)-one, which is a phosphodiesterase-4 inhibitor.
Detaljan opis izuma Detailed description of the invention
Spoj ovog izuma je prikazan formulom (I): The compound of this invention is represented by formula (I):
[image] [image]
ili njegove farmaceutski prihvatljive soli, gdje je or its pharmaceutically acceptable salts, where
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-C1-6alkil), -(C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirana sa 1-3 neovisna -C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent -C1 -6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, - O-N=C1-6 alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, -C1-6alkil(C3-6cikloalkil)(C3-6cikloalkil), -C1-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-aril, -C(O)-C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(-N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil opcionalno supstituiran s halogen, -C1-6alkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituirani sa l -6 neovisna halogen ili -OH supstituenta; R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(-N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, - C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH of the substituent;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje je svaki alkil opcionafno supstituiran sa 1-6 neovisna halogena, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C1-6alkil, -C1-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alki! opcionalno supstituiran sa 1-6 neovisna halogen ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and every one is alki! optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je fenil, piridil, pirimidil, indolil, kvinolinil, tienil, piridonil, oksazolil, oksadiazolil, tiazolil, tiadiazolil, ili imidazolil; ili njihovi oksidi kada je R8 heteroaril; ili H, -C1-6alkil, ili-C3-6cikloalkil, i svaki je alkil opcionalno supstituiran s 1-6 neovisna halogena, -N(C0-6alkil)(C0-6alkil),-N(C3-7cikloalkil)(C0-6alkil), -N(C3-7cikloalkil)(C3-7cikloalkil), N-heterocikloC4-7alkil, -SOn-(C1-6alkil), -SOn-(aril), ili -OH supstituenta. R 8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or their oxides when R 8 is heteroaryl; or H, -C1-6alkyl, or -C3-6cycloalkyl, and each alkyl is optionally substituted with 1-6 independent halogens, -N(C0-6alkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C0- 6alkyl), -N(C3-7cycloalkyl)(C3-7cycloalkyl), N-heterocycloC4-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituents.
U jednom aspektu, spoj ovog izuma je prikazan formulom (I) ili njegovom farmaceutski prihvatljivom soli, gdje In one aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili –C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil,-C(O)-C1-6alkil,-C(O)-aril,-(C0-6alkil)-SOn-(C1-6alkil), (C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirana sa 1-3 neovisna -C1-6alkil, -C1-6alkoksi, OH,-N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl,-C(O)-C 1-6 alkyl,-C(O)-aryl,-( C0-6alkyl)-SOn-(C1-6alkyl), (C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent -C1 -6alkyl, -C1-6alkyl, OH,-N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, - O-N=C1-6 alkyl, or halogen of the substituent;
R2 je odsutan; R2 is absent;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan; R3 is absent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C1-6alkil, -C1-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionalno supstituiran s 1-6 neovisna halogen ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je H. R8 is H.
U drugom aspektu, spoj ovog izuma je prikazan formulom (1) ili njegove farmaceutski prihvatljive soli, gdje je In another aspect, a compound of the present invention is represented by formula (1) or a pharmaceutically acceptable salt thereof, where
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirana sa 1 -3 neovisna -C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, -C1-6alkil(C3-6cikloalkil)(C3-6cildoalkil), -C1-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-ari1, -C(O)-C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(=N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil je opcionalno supstituiran sa halogen, -C1-6galkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogena ili -OH supstituenta; R2 is absent, H, halogen, -C1-6alkyl, -C3-6cycloalkyl, -C1-6alkyl(C3-6cycloalkyl)(C3-6cyldoalkyl), -C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogens or -OH of the substituent;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje je svaki alkil opcionalno supstituiran sa 1-6 neovisna halogen, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogen, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C0-6alkil, -C0-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i je svaki alkil opcionalno supstituiran sa 1-6 neovisna halogena ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 0-6 alkyl, -C 0-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je fenil, piridil, pirimidil, indolil, kvinolinil, ticnil, piridonil, oksazolil, oksadiazolil, tiazolil, tiadiazolil, ili imidazolil; ili njegov oksid kada R8 je heteroaril. R 8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thicnyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or its oxide when R 8 is heteroaryl.
U implementaciji drugog aspekta, spoj ovog izuma je prikazan formulom (I) ili njegove farmaceutski prihvatljive soli, gdje In an implementation of another aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirani sa 1-3 neovisna -C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, -C1-6alkil(C3-6cikloalkil)(C3-6cikloalkil), -C1-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-aril, -C(O)-C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(=N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil je opcionalno supstituiran sa halogenom, -C1-6alkil, -C1-6alkoksi, hiđroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogen ili -OH supstituenta; R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH of the substituent;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogen, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogen, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen,-C1-6alkil, -C1-6alkoksi, -SOn(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionalno supstituirani sa 1-6 neovisna halogen ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl) , and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je fenil. R 8 is phenyl.
U drugoj implementaciji drugog aspekta, spoj ovog izuma je prikazan formulom (I) ili njegove farmaceutski prihvatljive soli, gdje In another implementation of another aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6galkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirani sa 1-3 neovisna -C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-H(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6galkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-H(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl , -O-N=C1-6alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, -C1-6alkil(C3-6cikloalkil)(C3-6cikloalkil), -C0-6alkoksi, fenil, heteroaril, heterocikloC3-6alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-(C1-6alkil, -NHC(O)-aril, -(C(O)C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(=N-OH), -(C(N=NOH)C1-6alkil, -C0-6alkil(oksi)-C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil je opcionalno supstituirani sa halogen, -C1-6alkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituirani sa 1-6 neovisna halogen ili -OH supstituenta; R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 0-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-6 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-(C1-6alkyl, -NHC( O)-aryl, -(C(O)C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(=N-OH), -(C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)-C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1- 6 independent halogen or -OH substituents;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje je svaki alkil opcionalno supstituiran sa 1-6 neovisna halogena, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C1-6alkil, -C1-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogen ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je piridil, ili njegov oksid. R8 is pyridyl, or its oxide.
U još jednoj implementaciji drugog aspekta, spoj ovog izuma je prikazan formulom (I) ili njegovom farmaceutski prihvatljivom soli, gdje In yet another implementation of the second aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili -C3-6cikioalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil; -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirana sa 1-3 neovisna -C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl; -C1-6Alkoxy, -C2-6alkenyl, -C3-6alkynyl, -C(O)-C1-6alkyl, -C(O)-aryl, -(C0-6alkyl)-SOn-(C1-6alkyl), -( C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent -C1-6alkyl, -C1-6alkoxy, OH, -N(C0 -6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or a halogen substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, -C1-6alkil(C3-6cikloalkil)(C3-6cikloalkil), -C1-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-aril, -C(O)-C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(-N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil je opcionalno supstituiran sa halogen, -C1-6alkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil)} ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogena ili -OH supstituenta; R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(-N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl)} or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogens or -OH of the substituent;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogena, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C1-6alkil, -Cl-galkoksi, -SOn-(C1-ealkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionalno supstituiran sa l -6 neovisnih halogena ili -OH supstituenta; i R4, R5, R6, and R7 are each independently H, halogen, -C1-6alkyl, -C1-galkoxy, -SOn-(C1-ealkyl), nitro, CN, or -N(C0-6alkyl)(C0-6alkyl ), and each alkyl is optionally substituted with 1-6 independent halogens or -OH substituents; and
R8 je kvinolinil, ili njegov oksid. R8 is quinolinyl, or its oxide.
U još jednoj implementaciji drugog aspekta, spoj ovog izuma je prikazan formulom (I) ili njegove farmaceutski prihvatljive soli, gdje In yet another implementation of the second aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirana sa 1-3 neovisna -C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, R2 is absent, H, halogen, -C1-6alkyl, -C3-6cycloalkyl,
-C1-6alkil(C3-6cikloakil)(C3-6cikloalkil), -C0-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-aril, -C(O)-C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(=N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil)s gdje je fenil, heteroaril ili heterocikloC3-7alkil opcionalno supstituiran sa halogen, -C1-6alkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituiran sa l -6 neovisna halogena i li -OH supstituenta; -C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), -C0-6Alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, O-N=C1-6alkyl, -N(C0- 6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O)-aryl, -C(O)-C1-6alkyl, -C(O) -O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl)s where the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C1-6alkyl, -C1-6alkoxy, hydroxy, -N(C0-6alkyl)( C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1 -6 independent halogen and 1 -OH substituents;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogen, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogen, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C1-6alkil, -C1-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogena ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je tienil, ili njegov oksid. R8 is thienyl, or its oxide.
U drugoj implementaciji drugog aspekta, spoj ovog izuma je prikazan formulom (I) ili njegovom farmaceutski prihvatljivom soli, gdje In another embodiment of another aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirana sa 1-3 neovisna –C1-6alkil, -C1-6alkoksi, OH,-N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, -C1-6alkil(C3-6cikloalkil)(C3-6cikloalkil), -C1-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-aril, -C(O)-C1-6alkil, -C(O)-C1-6alkil, -C1-6alkil(=N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil je opcionalno supstituiran sa halogen, -C1-6alkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogen ili -OH supstituenta; R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl (oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C1 -6alkyl, -C1-6 alkoxy, hydroxy, -N(C0-6alkyl)(C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or - OH of the substituent;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogena, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C0-6alkil, -C1-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionalno supstituirani sa 1-6 neovisna halogena ili -OH supstiluenta; i R4, R5, R6, and R7 are each independently H, halogen, -C0-6alkyl, -C1-6alkyl, -SOn-(C1-6alkyl), nitro, CN, or -N(C0-6alkyl)(C0-6alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je tiazolil, ili njegov oksid. R8 is thiazolyl, or its oxide.
U trećem aspektu, spoj ovog izuma je prikazan formulom (1) ili njegovom farmaceutski prihvatljivom soli, gdje In a third aspect, a compound of the present invention is represented by formula (1) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(0)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6-alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituirana sa l -3 neovisna –C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6aIkii), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6-alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent –C1-6alkyl, -C1-6Alkoxy, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6aIkii), nitro, CN, =N-O-C1- 6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C0-6alkil, -C3-6cikloalkil, R2 is absent, H, halogen, -C0-6alkyl, -C3-6cycloalkyl,
-C1-6alkil(C3-6cikloalkil)(C3-6cikIoalkil), -C1-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-aril, -C(O)-C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(=N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil je opcionalno supstituiran sa halogen, -C1-6alkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogena ili -OH supstituenta; -C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), -C1-6Alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0 -6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O)-aryl, -C(O)-C1-6alkyl, -C(O )-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl) , or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl, or heterocycloC3-7alkyl is optionally substituted with halogen, -C1-6alkyl, -C1-6alkoxy, hydroxy, -N(C0-6alkyl )(C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogena, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C1-6alkil, -C1-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionalno supstituiran sa 1-6 neovisna halogen ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je-C3-6cikloalkil, opcionalno supstituiran sa 1-6 neovisna halogen, -N(C0-6alkil)(C0-6alkil), -N(C3-7cikloalkil)(C0-6alkil), -N(C3-7cikloalkil)(C3-7cikloalkil), N-heterocikloC3-7alkil, -SOn-(C1-6alkil), -SOn-(aril), ili -OH supstituenta. R8 is -C3-6cycloalkyl, optionally substituted with 1-6 independent halogen, -N(C0-6alkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C0-6alkyl), -N(C3-7cycloalkyl)( C3-7cycloalkyl), N-heterocycloC3-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituent.
U četvrtom aspektu, spoj ovog izuma je prikazan formulom (I) ili njegovom farmaceutski prihvatljivom soli, gdje In a fourth aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R je H, -C1-6alkil ili -C3-6cikloalkil; R is H, -C1-6alkyl or -C3-6cycloalkyl;
R1 je H, ili -C1-6alkil, -C3-6cikloalkil, -C1-6alkoksi, -C2-6alkenil, -C3-6alkinil, -C(O)-C1-6alkil, -C(O)-aril, -(C0-6alkil)-SOn-(C1-6alkil), -(C0-6alkil)-SOn-(aril), fenil, heteroaril, ili heterocikloC3-7alkil grupa, gdje je bilo koja od grupa opcionalno supstituiran sa 1-3 neovisna -C1-6alkil, -C1-6alkoksi, OH, -N(C0-6alkil)(C0-6alkil), -(C0-6alkil)-SOn-(C1-6alkil), nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, ili halogen supstituenta; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;
R2 je odsutan, H, halogen, -C1-6alkil, -C3-6cikloalkil, R2 is absent, H, halogen, -C1-6alkyl, -C3-6cycloalkyl,
-C1-6alkil(C3-6cikloalkil)(C3-6cikloalkil), -C1-6alkoksi, fenil, heteroaril, heterocikloC3-7alkil, nitro, CN, =N-O-C1-6alkil, -O-N=C1-6alkil, -N(C0-6alkil)(C0-6alkil), -NHSOn-(C1-6alkil), -NHC(O)-C1-6alkil, -NHC(O)-aril, -C(O)-C1-6alkil, -C(O)-O-C1-6alkil, -C1-6alkil(=N-OH), -C(N=NOH)C1-6alkil, -C0-6alkil(oksi)C1-6alkil-fenil, -SOnNH(C0-6alkil), ili -(C0-6alkil)-SOn-(C1-6alkil), gdje je fenil, heteroaril ili heterocikloC3-7alkil je opcionalno supstituiran sa halogenom, -C1-6alkil, -C1-6alkoksi, hidroksi, -N(C0-6alkil)(C0-6alkil), ili -C(O)-O-C1-6alkil, i svaki je alkil opcionahio supstituiran sa 1-6 neovisna halogena ili -OH supstituenta; -C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), -C1-6Alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0 -6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O)-aryl, -C(O)-C1-6alkyl, -C(O )-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl) . )(C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents;
n je 0, 1, ili 2; n is 0, 1, or 2;
R3 je odsutan, H, OH, -N(C0-6alkil)(C0-6alkil), halogen ili C1-6alkil, gdje je svaki alkil opcionalno supstituiran sa 1-6 neovisna halogena, OH, ili -N(C0-6alkil)(C0-6alkil) supstituenta; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;
R4, R5, R6, i R7 svaki neovisno je H, halogen, -C1-6alkil, -C1-6alkoksi, -SOn-(C1-6alkil), nitro, CN, ili -N(C0-6alkil)(C0-6alkil), i svaki je alkil opcionahio supstituiran sa 1-6 neovisna halogen ili -OH supstituenta; i R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and
R8 je -C1-6alkil, opcionalno supstituiran sa 1-6 neovisna halogena, -N(C0-6alkil)(C0-6alkil,-N(C3-7cikloalkil)(C0-6alkil), -N(C3-7cikloalkil)(C3-7cikloalkil), N-heterocikloC4-7alkil, -SOn-(C1-6alkil), -SOn-(aril), ili -OH supstituenta. R8 is -C1-6alkyl, optionally substituted with 1-6 independent halogens, -N(C0-6alkyl)(C0-6alkyl, -N(C3-7cycloalkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C3 -7cycloalkyl), N-heterocycloC4-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituent.
Kako se ovdje koristi, "alkil" kao i druge grupe s prefiksom "alk" kao što su, na primjer, alkoksi, alkanoil, alkenil, alkinil i slično, označavaju ugljikove lance koji mogu biti linearni ili razgranati ili njihove kombinacije. Primjeri alkil grupa sadržavaju metil, etil, propil, izopropil, butil, sek- i terc-butil, pentil, heksil, heptil i slično. "Alkenil", "alkinil" i drugi slični izrazi sadržavaju ugljikove lance koji sadržavaju najmanje jednu nezasićenu C-C vezu. As used herein, "alkyl" as well as other groups prefixed with "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, refer to carbon chains which may be straight or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other similar terms include carbon chains containing at least one unsaturated C-C bond.
Izraz "cikloalkil" označava karbociklike, koji ne sadržavaju heteroatome, obuhvaćaju mono-, bi- i tricikličke zasićene karbocikle, kao i sisteme kondenziranih prstenova.. Takvi sistemi kondenziranih prstenova mogu sadržavati jedan prsten, koji je djelomično ili potpuno nezasićen, kao što su benzenski prsteni, da se dobije sistem kondeziranih prstenova, kao stoje benokondenziranii karbocikli. Cikloalkil sadrži takve sisteme kondenziranih prstena, kao što su spirokondenzirani prsteni. Primjeri cikloalkila obuhvaćaju ciklopropil, ciklobutil, ciklopentil, cikloheksil, dekahidronaftalenil, adamantanil, indanil, indenil, fluorenil, 1,2,3,4-tetrahidronaftalenil i slično. Slično tome, "cikloalkenil" označava karbociklike koji ne sadržavaju heteroatome i najmanje jednu ne-aromatsku C-C dvostruku vezu, sadržavaju mono-, bi- i triciklički djelomično zasićene karbociklike, kao i benzokondenzirane cikloalkene. Primjeri cikloalkenila obuhvaćaju cikloheksenil, indenil, i slično. The term "cycloalkyl" denotes carbocyclics, which do not contain heteroatoms, including mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems may contain one ring, which is partially or fully unsaturated, such as benzene rings, to obtain a system of condensed rings, such as well-condensed carbocycles. Cycloalkyl contains such fused ring systems as spiro fused rings. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl, adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like. Similarly, "cycloalkenyl" refers to carbocyclics containing no heteroatoms and at least one non-aromatic C-C double bond, including mono-, bi- and tricyclic partially saturated carbocyclics, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
Izraz "cikloalkiloksi" ukoliko izrijekom nije naznačeno drugačije sadržava cikloalkil grupu, povezanu na oksi vezni atom. The term "cycloalkyloxy" unless otherwise indicated contains a cycloalkyl group attached to an oxy bonding atom.
Izraz "alkoksi", ukoliko izrijekom nije naznačeno drugačije, sadržava alkil grupu povezanu na oksi vezni atom. The term "alkoxy", unless expressly indicated otherwise, includes an alkyl group attached to an oxy bonding atom.
Izraz "aril", ukoliko izrijekom nije naznačeno drugačije, sadržava multiple sisteme prstenova, kao i jednostruke sisteme prstenova, kao što su, na primjer, fenil ili naftil. The term "aryl", unless otherwise indicated, includes multiple ring systems as well as single ring systems, such as, for example, phenyl or naphthyl.
Izraz "ariloksi", ukoliko izrijekom nije naznačeno drugačije, sadržava multiple sisteme prstenova, kao i jednostruke sisteme prstenova, kao što su, na primjer, fenil ili naftil, povezane kroz oksi vezni atom, na vezno mjesto. The term "aryloxy", unless expressly indicated otherwise, includes multiple ring systems as well as single ring systems, such as, for example, phenyl or naphthyl, linked through an oxy bonding atom to the bonding site.
Izraz "C0-C6alkil" obuhvaća alkile, koji sadržavaju 6, 5, 4, 3, 2, 1, ili nijedan ugljikov atom. Alkil bez ugljikovih atoma je supstituent vodikovog atoma, kada je alkil terminalni dio. Alkil bez ugljikovih atoma je direktno vezan, kada je alkil dio za premošćivanje. The term "C 0 -C 6 alkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. Alkyl without carbon atoms is a hydrogen atom substituent when the alkyl is the terminal moiety. Alkyl without carbon atoms is directly attached, when the alkyl is a bridging moiety.
Izraz "hetero", ukoliko izrijekom nije naznačeno drugačije, sadržava jedan ili više O, S, ili N atoma. Na primjer, heterocikloalkil i heteroaril sadržavaju sisteme prstenova koji sadržavaju jedan ili više O, S, ili N atoma u prstenu, uključujući smjese takvih atoma. Heteroatomi mijenjaju ugljikove atome u prstenu. Stoga, na primjer, heterocikloCsalkil je peto-člani prsten koji sadrži od 5 do nijednog ugljikovog atoma. The term "hetero", unless otherwise indicated, contains one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl contain ring systems containing one or more O, S, or N ring atoms, including mixtures of such atoms. Heteroatoms replace the carbon atoms in the ring. Thus, for example, heterocycloCsalkyl is a five-membered ring containing from 5 to no carbon atoms.
Primjeri heteroarila sadržavaju, na primjer, piridinil, kvinolinil, izokvinolinil, piridazinil, pirimidinil, pirazinil, kvinoksalinil, furil, benzofuril, đibenzofuril, tienil, benzotienil, piirolil, indolil, pirazolil, indazolil, oksazolil, izoksazolil, tiazolil, izotiazolil, imidazolil, benzimidazoHl, oksadiazolil, tiadiazolil, triazolil, tetrazolil. Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazoHl. , oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.
Izraz "heteroariloksi", ukoliko izrijekom nije naznačeno drugačije, opisuje heteroaril grupu, povezanu kroz oksi vezni atom, na vezno mjesto. The term "heteroaryloxy", unless otherwise indicated, describes a heteroaryl group attached through an oxy bonding atom to the bonding site.
Primjeri heteroaril(C1-6)alkil obuhvaćaju, na primjer, furilmetil, furiletil, tienilmetil, tieniletil, pirazolilmetil, oksazolilmetil, oksazoliletil, izoksazolilmetil, tiazolilmetil, tiazoliletil, imidazolilmetil, imidazoliletil, benzimidazolilmetil, oksadiazolilmetil, oksadiazoliletil, tiadiazolilmetil, tiadiazoliletil, triazolilmetil, triazoliletil, tetrazolilmetil, tetrazolil etil, piridinilmetil, piridiniletil, piridazinilmetil, pirimidinilmetil, pirazinilmetil, kvinolinilmetil, izokvinolinilmetil i kvinoksalinilmetil. Examples of heteroaryl(C1-6)alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl. , tetrazolylmethyl, tetrazolyl ethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
Primjeri heterocikloC3-7alkila sadržavaju, na primjer, azetidinil, pirrolidinil, piperidinil, perhidroazepinil, piperazinil, morfolinil, tetrahidrofuranil, imidazolinil, pirolidin-2-on, piperidin-2-on, i tiomorfolinil. Examples of heterocycloC3-7alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
Izraz ''N-heterocikloC4-7alkil'' opisuje nearil heterocikličke spojeve sa 3-6 ugljikovih atoma i jednim dušikovim atomom koji formiraju prsten. Primjeri obuhvaćaju azetidinil, pirrolidinil, piperidinil, i perhidroazepinil. The term "N-heterocycloC4-7alkyl" describes non-aryl heterocyclic compounds with 3-6 carbon atoms and one nitrogen atom forming a ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepinyl.
Primjeri aril(C1-6)alkil obuhvaćaju, na primjer, fenil(C1-6)alkil, i naftil(-C1-6)alkil. Examples of aryl(C 1-6 )alkyl include, for example, phenyl(C 1-6 )alkyl, and naphthyl(-C 1-6 )alkyl.
Primjeri heterocikloC3-7alkilkarboniI(C1-6)alkil obuhvaćaju, na primjer, azetidinil karbonil(C1-6)alkil, pirrolidinil karbonil(C1-6)alkil, piperidinil karbonil(C1-6)alkil, pjperazinil karbonil(C1-6)alkil, morfolinil karbonil(C1-6)alkil, i tiomorfolinil karbonil(C1-6)alkil. Examples of heterocycloC3-7alkylcarbonyl(C1-6)alkyl include, for example, azetidinylcarbonyl(C1-6)alkyl, pyrrolidinylcarbonyl(C1-6)alkyl, piperidinylcarbonyl(C1-6)alkyl, piperazinylcarbonyl(C1-6)alkyl , morpholinylcarbonyl(C1-6)alkyl, and thiomorpholinylcarbonyl(C1-6)alkyl.
Izraz "amin", ukoliko izrijekom nije naznačeno dragačije, sadržava primarne, sekundarne i tercijarne amine. The term "amine", unless otherwise indicated, includes primary, secondary and tertiary amines.
Ukoliko nije drugačije naznačeno, izraz "karbamoil" obuhvaća -NHC(O)OC1-C4alkil, i -OC(O)NHCl-C4alkil. Unless otherwise indicated, the term "carbamoyl" includes -NHC(O)OC1-C4alkyl, and -OC(O)NHCl-C4alkyl.
Izraz "halogen" sadržava fluor, klor, brom i jod atome. The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.
Izraz "opcionalno supstituirani" obuhvaća kako supstituirane i nesupstituirane. Stoga, na primjer, opcionabio supstituirani aril može predstavljati pentafluorofenil ili fenil prsten. Nadalje, supstitucija može biti na bilo kojoj od grupa. Na primjer, supstituirani aril(C1-6)alkil obuhvaća supstituciju na aril grupi, kao i supstituciju na alkil grupi. The term "optionally substituted" includes both substituted and unsubstituted. Thus, for example, an optionally substituted aryl may represent a pentafluorophenyl or a phenyl ring. Furthermore, the substitution can be on any of the groups. For example, substituted aryl(C 1-6 )alkyl includes substitution on the aryl group as well as substitution on the alkyl group.
Izraz "oksid" heteroaril grupe je korišten u dobro poznatom kemijskom značenju i sadržavaju, na primjer, N-okside dušikovih heteroatoma. The term "oxide" of a heteroaryl group is used in the well-known chemical sense and includes, for example, N-oxides of nitrogen heteroatoms.
Spojevi ovdje opisani sadržavaju jednu ili više dvostrukih veza i mogu stoga dati cis/trans izomere, kao i druge konformacijske izomere. Predmetni izum obuhvaća sve takve moguće izomere kao i smjese takvih izomera. The compounds described herein contain one or more double bonds and may therefore give cis/trans isomers as well as other conformational isomers. The subject invention includes all such possible isomers as well as mixtures of such isomers.
Spojevi ovdje opisani mogu sadržavati jedan ili više asimetričkih centara i mogu stoga dati diastereomere i optičke izomere. Predmetni izum obuhvaća sve takve moguće diastereomere, kao i njihove racematske smjese, njihove uglavnom čiste otopljene enantiomere, sve moguće geometrijske izomere, i njihove farmaceutski prihvatljive soli. Gornja Formula I je prikazana bez određene stereokemije na nekim pozicijama. Predmetni izum obuhvaća sve stereoizomere Formule I i njene farmaceutski prihvatljive soli. Nadalje, smjese stereoizomera kao i izolirani specifični stereoizomeri su također uključeni. Tijekom sintetičkih postupaka korištenih u pripravi takvih spojeva, ili koristeći racemizaciju ili epimerizaciju -postupke koji su poznati stručnim osobama, produkti takvih postupaka mogu biti smjese stereoizomera. The compounds described herein may contain one or more asymmetric centers and may therefore give diastereomers and optical isomers. The subject invention encompasses all such possible diastereomers, as well as their racemic mixtures, their mostly pure dissolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. The above Formula I is shown without certain stereochemistry at some positions. The subject invention includes all stereoisomers of Formula I and its pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the synthetic procedures used in the preparation of such compounds, or using racemization or epimerization - procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.
Izraz "farmaceutski prihvatljive soli" odnosi se na soli pripravljene od farmaceutski prihvatljivih ne-toksičkih baza ili kiselina. Kada je spoj predmetnog izuma kiseo, odgovarajuća sol može biti prikladno pripravljena od farmaceutski prihvatljive ne-toksične baze, uključujući neorganske i organske baze. Soli izvedene od takvih neorganskih baza obuhvaćaju aluminijeve, amonijeve, kalcijeve, kupro, kupri, fero, feri, litijeve, magnezijeve, mangano i mangani, kalijeve, natrijeve, cinkove i slične soli. Naročito poželjne su amonijeve, kalcijeve, magnezijeve, kalijeve i natrijeve soli. Soli izvedene od farmaceutski prihvatljivih organskih ne-toksičnih baza obuhvaćaju soli primarnih, sekundarnih i tercijarnih amina, kao i cikličkih amina i supstituiranih amina, kao što su prirodni prstenasti i sintetizirani supstituirani amini. Druge farmaceutski prihvatljive organske ne-toksične baze od kojih se mogu formirati soli obuhvaćaju jonsko izmijenjvačke smole ionske, kao što su, na primjer, arginin, betain, kafein, kolin, N,N'-dibenziletilendiamin, dietilarnin, 2-dietilaminoetanol, 2-dimetilaminoetanol, etanolamrn, etilendiamin, N-etilmorfolin, N-etilpiperidin, glukamin, glukozamin, histidin, hidrabamin, izopropilamin, lizin, metilglukamin, morfolin, piperazin, piperidin, poliamin smole, prokain, purini, teobromin, trietilamin, trimetilamin, tripropilamin, trometamin i slično. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, the corresponding salt may be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, cupric, cupric, ferrous, ferric, lithium, magnesium, manganese and manganese, potassium, sodium, zinc and similar salts. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring cyclic and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ionic exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylarnine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and similar.
Kada je spoj predmetnog izuma baza, odgovarajuće soli mogu biti prikladno pripravljene od farmaceutski prihvatljivih ne-toksičnih kiselina, uključujući neorganske i organske kiseline. Takve kiseline obuhvaćaju, na primjer, octenu, benzensulfonsku, benzojevu, kamforsulfonsku, limunsku, etansulfonsku, mravlju, glukonsku, glutaminsku, bromovodičnu, klorovodičnu, izetionsku, mlječnu, maleinsku, jabučnu, bademovu, metansulfonskUj mucinsku, dušičnu, pamoičku, pantotensku, fosfornu, sukcinatnu, sumpornu, vinsku, p-toluensu]fonsku kiselinu i slično, Naročito poželjne su benzensulfonska, Hmunska, bromovodična, klorovodična, maleinska, fosforna, sumporna, i vinska kiselina. When the compound of the present invention is a base, the corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulphonic acid and the like, particularly preferred are benzenesulfonic, humic, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
Farmaceutski pripravci predmetnog izuma sadržavaju spoj prikazan formulom I (ili njegove farmaceutski prihvatljive soli) kao aktivan sastojak, farmaceutski prihvatljiv nosač i opcionalno druge terapeutske sastojke ili adjuvante. Takvi dodatni terapijski sastojci sadržavaju, na primjer, i) antagoniste leukotrien receptora, ii) inhibitore biosinteze leukotriena, iii) kortikosteroide, iv) antagoniste H1 receptora, v) agoniste beta 2 adrenoceptora, vi) COKS-2 selektivne inhibitore, vii) statine, viii) ne-steroidne protu-upalne lijekove ("NSAID"), i ix) M2/M3 antagoniste. Pripravci uključuju sastave pogodne za oralno, rektalno, lokalno, i parenteralno (uključujući supkutano, intramuskularno, i intravenozno) davanje, iako najpogodniji put u svakom pojedinom slučaju ovisit će o domaćinu, i prirodi i ozbiljnosti stanja za koje se aktivni sastojak daje. Farmaceutski pripravci mogu biti prikladno priređeni u obliku jediničnih doza i pripravljeni po bilo kojoj od metoda poznatih u farmaceutskoj struci. The pharmaceutical preparations of the present invention contain the compound represented by formula I (or its pharmaceutically acceptable salts) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COKS-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs ("NSAIDs"), and ix) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most convenient route in each case will depend on the host, and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical preparations may be conveniently prepared in the form of unit doses and prepared by any of the methods known in the pharmaceutical art.
Kreme, masti, želei, otopine, ili suspenzije koji sadržavaju spoj Formule I mogu se koristiti za lokalnu uporabu. Sredstva za ispiranje usta i grla su obuhvaćeni kao lokalna uporaba u svrhu ovog izuma. Creams, ointments, jellies, solutions, or suspensions containing a compound of Formula I may be used for topical application. Mouth and throat rinses are encompassed as topical use for the purposes of this invention.
Razina doziranja od oko 0.001mg/kg do oko 140mg/kg tjelesne težine dnevno, su korisne u liječenju stanja kao što su i) plućni poremećaji kao Sto su astma, kronični bronhitis, kronična opstruktivna plućna bolest (COPD), sindrom respiratornog poremećaja kod odraslih, sindrom respiratornog poremećaja kod djece, kašalj, kronična opstruktivna plućna bolest kod životinja, sindrom respiratornog poremećaja kod odraslih, i sindrom respiratornog poremećaja kod djece, ii) gastrointestinalni poremećaji kao što su ulcerativni kolitis, Crohn-ova bolest, i hipersekrecija želučane kiseline, iii) infektivne bolesti kao što su bakterijski, gljivično ili virusno izazvane sepse ili septički šok, endotoksički šok (i srodna stanja kao što su laminitis i grčevi kod konja), te septički šok, iv) neurološki poremećaji kao što su ozljede leđne moždine, povrede glave, neurogene upale, bolovi, i reperfuzijskih povreda mozga, v) upalni poremećaji kao što su psorijatrijski artritis, reumatski artritis, ankilozni spondilitis, osteoartritis, upala i citokin-posredovana kronična degeneracija tkiva, vi) alergijski poremećaji kao što su alergijski rinitis, alergijski konjuktivitis, i eozinofilni granulom, vii) psihijatrijski poremećaji kao što su depresija, oštećenje memorije, i monopolarna depresija, viii) neurodegenerativni poremećaji kao što su Parkinsonova bolest, Alzheimerova bolest, akutna i kronična multipla skleroza, ix) Dermatološki poremećaji kao što su psoriaza i druge benigne ili maligne proliferativne kožne bolesti, atopički dermatitis, i urticaria, x) onkološke bolesti kao što su rak, rast tumora i kancerogena invazija normalnanog tkiva, xi) metabolički poremećaji kao što su diabetes insipidus, xii) koštani poremećaja kao što su osteoporoza, xiii) kardiovaskularni poremećaji kao što su arterijska restenoza, arteroskleroza, reperfuzijska povreda miokarda, i xiv) drugi poremećaja kao što su kronični glomerulonefritis, vemalni konjuktivitis, odbacivanje transplantata i implantata, te kaheksija - koji su responzivni na PDE4 inhibiciju, ili alternativno oko 0.05mg do oko 7g po pacijentu dnevno. Na primjer, upale mogu biti djelotvorno liječene davanjem od oko 0.01mg do 50mg spoja po kilogramu tjelesne težine dnevno, ili alternativno oko 0.5mg do oko 2.5g po pacijentu dnevno. Nadalje, razumije se da PDE4 inhibirajući spojevi ovog izuma mogu biti davani u profilaktički djelotvornim razinama doziranja, radi sprječavanja gore navedenih stanja. Dosage levels from about 0.001mg/kg to about 140mg/kg of body weight per day are useful in the treatment of conditions such as i) lung disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), respiratory disorder syndrome in adults , respiratory distress syndrome in children, cough, chronic obstructive pulmonary disease in animals, respiratory distress syndrome in adults, and respiratory distress syndrome in children, ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and gastric acid hypersecretion, iii ) infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and colic in horses), and septic shock, iv) neurological disorders such as spinal cord injuries, head injuries , neurogenic inflammation, pain, and brain reperfusion injuries, v) inflammatory disorders such as psoriatic arthritis, rheumatic arthritis, ankylosis sp ntilitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissue, xi) metabolic disorders such as diabetes insipidus, xii) bone disorders such as osteoporosis, xiii) cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and xiv) other disorders such as chronic glomerulonephritis , vemal conjunctivitis, rejection of transplants and implants, and cachex ija - which are responsive to PDE4 inhibition, or alternatively about 0.05mg to about 7g per patient per day. For example, inflammation can be effectively treated by administering from about 0.01mg to about 50mg of the compound per kilogram of body weight per day, or alternatively from about 0.5mg to about 2.5g per patient per day. Furthermore, it is understood that the PDE4 inhibiting compounds of the present invention may be administered at prophylactically effective dosage levels to prevent the aforementioned conditions.
Količina aktivnog sastojka, koja se može kombinirati sa nosivim materijalima, da se dobije jedinični oblik doziranja, razlikovat će se ovisno o liječenom domaćinu i specifičnom načinu davanja. Na primjer, formulacija namijenjena za oralno davanje ljudima može prikladno sadržavati od oko 0.5mg do oko 5g aktivnog agensa, s odgovarajućom prikladnom količinom nosivog materijala koji mogu varirati od oko 5 do oko 95 postotaka ukupnog sastava. Jedinični oblici doziranja općenito sadržavaju između od oko 0.01mg do oko 1000mg aktivnog sastojka, obično 0.01mg, 0.05mg, 0.25mg, 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg ili 1000mg. The amount of active ingredient that can be combined with the carrier materials to form a unit dosage form will vary depending on the host treated and the specific route of administration. For example, a formulation intended for oral administration to humans may suitably contain from about 0.5mg to about 5g of active agent, with a corresponding suitable amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms generally contain between about 0.01mg to about 1000mg of active ingredient, typically 0.01mg, 0.05mg, 0.25mg, 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.
Razumije se, međutim, da specifične razine doza za svakog pojedinog pacijenta ovise o raznim faktorima, uključujući starost, tjelesnu težinu, opće zdravlje, spol, prehranu, vrijeme davanja, put davanja, brzina ekskrecije, kombinacije lijekova i ozbiljnosti specifične bolesti koja se liječi. It is understood, however, that specific dosage levels for each individual patient depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations, and severity of the specific disease being treated.
U praksi, spojevi ovog izuma prikazani formulom I, ili njenim farmaceutski prihvatljivim solima, mogu biti kombinirati kao aktivni sastojci u smjesi s farmaceutskim nosačem, prema konvencionalnoj farmaceutskoj tehnici. Nosači mogu biti različitog oblika, ovisno o željenom obliku davanja pripravka, npr. oralno ili parenteralno (uključujući intravenozno). Stoga, farmaceutski pripravci predmetnog izuma mogu biti priređeni kao diskretne jedinice pogodne za oralno davanje kao što su kapsule, pilule ili tablete, koji sadržavaju predodređenu količinu aktivnog sastojka. Nadalje, pripravci mogu biti priređeni kao prašak, granule, otopina, suspenzija u vodenoj tekućini, kao ne-vodena tekućina, kao emulzija ulje-u-vodi, ili kao emulzija voda-u-ulju. Uz uobičajene oblike doziranja, gore opisane, spoj prikazan formulom I, ili njegove farmaceutski prihvatljive soli, mogu biti davani kontroliranim otpuštanjem i/ili kroz uređaje za davanje. Pripravci mogu biti pripravljeni po bilo kojoj od farmaceutskih metoda. Općenito, takve metode sadržavaju korak koji dovodi aktivni sastojak u vezu s nosačem, koji se sastoji od jednog ili više potrebnih sastojaka. Općenito, pripravci su pripravljeni uniformnim i dubokim miješanjem aktivnog sastojka sa tekućim nosačima ili fino podijeljenim krutim nosačima ili oboje. Produkt može tada biti prikladno oblikovan. In practice, the compounds of this invention represented by formula I, or its pharmaceutically acceptable salts, can be combined as active ingredients in a mixture with a pharmaceutical carrier, according to conventional pharmaceutical technique. Carriers can be of different forms, depending on the desired form of administration of the preparation, eg oral or parenteral (including intravenous). Therefore, the pharmaceutical preparations of the present invention can be prepared as discrete units suitable for oral administration such as capsules, pills or tablets, which contain a predetermined amount of the active ingredient. Furthermore, the preparations can be prepared as a powder, granules, solution, suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil emulsion. In addition to the usual dosage forms described above, the compound represented by formula I, or its pharmaceutically acceptable salts, can be administered by controlled release and/or through delivery devices. Preparations can be prepared by any of the pharmaceutical methods. In general, such methods include a step that brings the active ingredient into contact with a carrier, which consists of one or more of the necessary ingredients. In general, the compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be suitably shaped.
Stoga, farmaceutski pripravci ovog izuma mogu sadržavati farmaceutski prihvatljiv nosač i spoj ili farmaceutski prihvatljivu sol Formule I. Spojevi Formule I, ili njene farmaceutski prihvatljive soli, mogu također biti uključeni u farmaceutske pripravke u kombinaciji sa jednim ili više drugih terapijski aktivnih spojeva. Therefore, the pharmaceutical compositions of this invention may contain a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or a pharmaceutically acceptable salt thereof, may also be included in the pharmaceutical compositions in combination with one or more other therapeutically active compounds.
Farmaceutski nosači koji mogu biti korišteni su, na primjer, krutina, tekućina, ili plin. Primjeri krutih nosača obuhvaćaju laktozu, terra alba, sukrozu, talk, želatinu, agar, pektin, akaciju, magnezij stearat, te stearinsku kiselinu. Primjeri tekućih nosača su šećerni sirup, ulje kikirikija, maslinovo ulje, te voda. Primjeri plinovitih nosača obuhvaćaju ugljični dioksid i dušik. Pharmaceutical carriers that may be used are, for example, solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
U pripravi sastava za oralni oblik doziranja, mogu se koristiti svi pogodni farmaceutski mediji. Na primjer voda, glikoli, ulja, alkoholi, agensi okusa, konzervansi, agensi boje i slično mogu biti korišteni, da se dobiju oralni tekući pripravci, kao što su suspenzije, elksiri i otopine; dok nosači kao Što su škrobovi, šećeri, mikrokristalne celuloze, razrjeđivači, agensi granuliranja, lubrikanti, veziva, dezintegrativni agensi, i slično mogu biti korišteni da se dobiju oralni kruti pripravci kao što su praškovi, kapsule i tablete. Tablete i kapsule su poželjne oralne jedinične doze, radi lakoće uzimanja, kada se koriste kruti farmaceutski nosači. Opcionalno, tablete mogu biti presvučene standardnim vodenim ili bezvodnim tehnikama. In the preparation of the composition for the oral dosage form, all suitable pharmaceutical media can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to produce oral liquid preparations, such as suspensions, elixirs, and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to provide oral solid preparations such as powders, capsules and tablets. Tablets and capsules are preferred oral unit doses, for ease of administration, when solid pharmaceutical carriers are used. Optionally, the tablets can be coated using standard aqueous or anhydrous techniques.
Tableta koja sadrži sastave ovog izuma može biti pripravljena kompresijom ili u kalupu, opcionalno sa jednim ili više dodatnih sastojka ili adjuvanta. Komprimirane tablete mogu biti pripravljene kompresijom, u pogodnom stroju, aktivni sastojak u slobodnom obliku, kao što su prašak ili granule, opcionalno miješano s vezivom, lubrikantom, inertnim razrjeđivačem, površinski aktivnim ili disperzivnim agensom. Tablete iz kalupa mogu biti pripravljene u pogodnom stroju, smjesa praškastog spoja ovlažena sa inertnim tekućim razrjeđivačem. Svaka tableta poželjno sadržava od oko 0.1mg do oko 500mg aktivnog sastojka i svaka pilula ili kapsula poželjno sadržava od oko 0.1mg do oko 500mg aktivnog sastojka. A tablet containing the compositions of this invention may be prepared by compression or in a mold, optionally with one or more additional ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in free form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Tablets from the mold can be prepared in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1mg to about 500mg of active ingredient and each pill or capsule preferably contains from about 0.1mg to about 500mg of active ingredient.
Farmaceutski pripravci predmetnog izuma pogodni za parenteralno davanje mogu biti pripravljeni kao otopine ili suspenzije aktivnog spoja u vodi. Pogodni surfaktant može biti uključen, kao što su, na primjer, hidroksipropilceluloza. Disperzije mogu također biti pripravljene u glicerolu, tekućem polietilen glikolu, te njihovim smjesama u ulju. Nadalje, konzervans može biti uključen radi sprječavanja štetnog rasta mikroorganizama. Pharmaceutical preparations of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. A suitable surfactant may be included, such as, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and their mixtures in oil. Furthermore, a preservative may be included to prevent the harmful growth of microorganisms.
Farmaceutski pripravci predmetnog izuma pogodni za injektabilnu uporabu sadržavaju sterilnu vodenu otopinu ili disperziju. Nadalje, pripravci mogu biti u obliku sterilnih praškova za ad hoc pripravu takvih sterilnih injektabilnih otopina ili disperzija. U svim slučajevima, konačni injektabilni oblik mora biti sterilan i mora biti djelotvorna tekućina za laku siringabilnost. Farmaceutski pripravci moraju biti stabilni, tijekom proizvodnje i skladištenja; stoga je poželjna zaštita protiv kontaminirajućeg djelovanja mikroorganizama, kao što su bakterije i gljivice. Nosači mogu biti otapalo ili disperzivni medij, koji sadržava, na primjer vodu, etanol, poliol (npr. glicerol, propilen glikol i tekućina polietilen glikol), biljna ulja, te njihove pogodne smjese. Pharmaceutical preparations of the present invention suitable for injectable use contain a sterile aqueous solution or dispersion. Furthermore, the preparations can be in the form of sterile powders for the ad hoc preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be an effective fluid for easy syringability. Pharmaceutical preparations must be stable during production and storage; therefore, protection against the contaminating action of microorganisms, such as bacteria and fungi, is desirable. Carriers can be a solvent or dispersing medium, containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Farmaceutski pripravci predmetnog izuma mogu biti u obliku pogodnom za lokalnu uporabu kao što su, na primjer aerosol, krema, mast, losion, prašak, ili slično. Nadalje, pripravci mogu biti u obliku pogodnom za uporabu u transdermalnim napravama. Ove formulacije mogu biti pripravljene, koristeći spoj prikazan formulom I ovog izuma, ili njegovim farmaceutski prihvatljivim solima, putem konvencionalnih procesnih metoda. Kao primjer krema ili mast je pripravljena miješanjem hidrofilnih materijala i vode, zajedno sa oko 5 težinskih% do oko 10težinskih % spoja, da se dobije krema ili mast sa željenom konzistencijom. The pharmaceutical preparations of the subject invention can be in a form suitable for local use, such as, for example, an aerosol, cream, ointment, lotion, powder, or the like. Furthermore, the compositions may be in a form suitable for use in transdermal devices. These formulations may be prepared using a compound represented by formula I of the present invention, or a pharmaceutically acceptable salt thereof, by conventional process methods. As an example, a cream or ointment is prepared by mixing hydrophilic materials and water, together with about 5% by weight to about 10% by weight of the compound, to obtain a cream or ointment of the desired consistency.
Farmaceutski pripravci ovog izuma mogu biti u obliku pogodnom za rektalno davanje, gdje je nosač krutina. Poželjno je da smjesa formira jedinične doze supozitorija. Pogodni nosači sadržavaju kokosov maslac i druge materijale često korištene u struci. Supozitoriji mogu biti prikladno pripravljeni prvo miješanjem sastava sa omekšalim ili otopljenim nosač(ima) uz hlađenje i oblikovanjem u kalupima. The pharmaceutical compositions of this invention may be in a form suitable for rectal administration, where the carrier is a solid. Preferably, the mixture forms suppository unit doses. Suitable carriers include coconut butter and other materials commonly used in the art. Suppositories may be conveniently prepared by first mixing the composition with the softened or dissolved carrier(s) while cooling and forming in molds.
Dodamo na ranije spomenute sastojke nosača, farmaceutske formulacije opisane gore mogu prikladno sadržavati, jedan ili više dodatnih sastojaka nosača, kao što su razrijeđivači, puferi, agensi okusa, veziva, površinski aktivne agense, agense za zgušnjavanje, lubrikante, konzervanse (uključujući anti-oksidanse) i slično. Nadalje, drugi adjuvanti mogu biti uključeni da formulacija bude izotonična s krvi primatelja. Pripravci koji sadržavaju spoj opisan formulom I, ili njegovu farmaceutski prihvatljivu sol, mogu također biti pripravljeni u obliku praška ili tekućeg koncentrata. In addition to the previously mentioned carrier ingredients, the pharmaceutical formulations described above may conveniently contain one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickening agents, lubricants, preservatives (including antioxidants ) and similar. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the recipient. Preparations containing the compound described by formula I, or its pharmaceutically acceptable salt, can also be prepared in the form of a powder or liquid concentrate.
Spojevi i farmaceutski pripravci ovog izuma pokazuju biološku aktivnost kao PDE4 inhibitori. Sukladno tome, drugi aspekt izuma jest liječenje sisavaca, na primjer, i) plućnih poremećaja kao što su astma, kronični bronhitis, kronična opstruktivna plućna bolest (COPD), sindrom respiratornog poremećaja kod odraslih, sindrom respiratornog poremećaja kod djece, kašalj, kronična opstruktivna plućna bolest kod životinja, sindrom respiratornog poremećaja kod odraslih, i sindrom respiratornog poremećaja kod djece, ii) gastrointestinalnih poremećaja kao što su ulcerativni kolitis, Crohn-ova bolest, i hipersekrecija želučane kiseline, iii) infektivnih bolesti kao što su bakterijske, gljivično ili virusno izazvane sepse ili septički šok, endotoksički šok (i srodna stanja kao što su laminitis i grčevi u konja), i septički šok, iv) neuroloških poremećaja kao što su ozljede leđne moždine, povrede glave, neurogene upale, bolovi, i reperflizijskih povreda mozga, v) upalnih poremećaja kao što su psorijatrij ski artritis, reumatski artritis, ankilozni spondilitis, osteoartritis, upalna i citokin-posredovana kronična degeneracija tkiva, vi) alergijskih poremećaja kao što su alergijski rinitis, alergijski konjuktivitis, i eozinofilni granulom, vii) psihijatrijskih poremećaja kao što su depresija, oštećenje memorije, i monopolarna depresija, viii) neurodegenerativnih poremećaja, kao što su Parkinson-ova bolest, Alzheimer-ova bolest, akutna i kronična multipla skleroza, ix) dermatoloških poremećaja kao što su psoriaza i druge benigne ili maligne proliferativne kožne bolesti, atopički dermatitis, i urticaria, x) onkoloških bolesti kao što su rak, rast tumora i kancerogena invazija normalnanog tkiva, xi) metaboličkih poremećaja kao što su diabetes insipidus, xii) koštanih poremećaja kao Što su osteoporoza, xiii) kardiovaskularnih poremećaja kao što su arterijska restenoza, arteroskleroza, reperfuzijske povrede miokarda, i xiv) drugih poremećaja, kao što su kronični glomerulonefritis, vemalni konjuktivitis, odbacivanje transplantata i implantata, i kaheksija - bolesti koji su podložne poboljšanju inhibicijom PDE4 izoenzima, te rezultirajućih povišenih cAMP razina - davanjem djelotvorne količine spojeva ovog izuma. Izraz "sisavci" obuhvaća ljude, kao i druge životinje kao što su, na primjer, psi, mačke, konji, svinje, i stoka. Shodno tome, razumije se da liječenje sisavaca pored ljudi, jest liječenje klinički koreliranih bolesti onima koje su gore navedene u primjerima za bolesti ljudi. The compounds and pharmaceutical compositions of the present invention exhibit biological activity as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment of mammals, for example, i) pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, pediatric respiratory distress syndrome, cough, chronic obstructive pulmonary disease disease in animals, respiratory distress syndrome in adults, and respiratory distress syndrome in children, ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and colic in horses), and septic shock, iv) neurological disorders such as spinal cord injuries, head injuries, neurogenic inflammation, pain, and reperfusion injuries of the brain, v ) inflammatory disorders such as psoriatic arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, inflammatory and cytokine -mediated chronic tissue degeneration, vi) allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) oncological diseases such as cancer, tumor growth and cancerous invasion normal tissue, xi) metabolic disorders such as diabetes insipidus, xii) bone disorders such as osteoporosis, xiii) cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and xiv) other disorders, such as chronic glomerulonephritis, vemal conjunctivitis, rejection of transplants and implants, and cachexia - underlying diseases not improving by inhibiting the PDE4 isoenzyme, and the resulting elevated cAMP levels - by administering an effective amount of the compounds of this invention. The term "mammals" includes humans as well as other animals such as, for example, dogs, cats, horses, pigs, and livestock. Accordingly, it is understood that the treatment of mammals in addition to humans is the treatment of clinically correlated diseases to those listed above in the human disease examples.
Nadalje, kako je gore opisano, spojevi ovog izuma mogu biti korišteni u kombinaciji sa drigim terapijskim spojeva. Posebno, kombinacije PDE4 inhibirajućeg spoja ovog izuma mogu biti korišteni u kombinaciji sa i) antagonistima leukotrien receptora, ii) inhibitorima leukotrien biosinteze, iii) COKS-2 selektivnim inhibitorima, iv) statinima, v) NSAID, vi) M2/M3 antagonisti, vii) kortikosteroidima, viii) H1 antagonistima (histamin) receptora i ix) agonistima beta 2 adrenoceptor. Furthermore, as described above, the compounds of this invention may be used in combination with other therapeutic compounds. In particular, combinations of the PDE4 inhibiting compound of the present invention can be used in combination with i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) COKS-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii ) corticosteroids, viii) H1 antagonists (histamine) receptors and ix) beta 2 adrenoceptor agonists.
Stoga, na primjer, plućni poremećaji kao što su astma, kronični bronhitis, kronična opstruktivna plućna bolest (COPD), sindrom respiratornog poremećaja kod odraslih, sindrom respiratornog poremećaja kod djece, kašalj, kronična opstruktivna plućna bolest kod životinja, sindrom respiratornog poremećaja kod odraslih, i sindrom respiratornog poremećaja kod djece mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koje mogu sadržavati mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka spoja predmetne prijave, ili njegovih farmaceutski prihvatljivih soli, davani jednom, dvaput, ili triput dnevno. Therefore, for example, lung disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, pediatric respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, adult respiratory distress syndrome, and respiratory disorder syndrome in children can be suitably treated with capsules, pills or tablets, which can contain mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salts, given once, twice, or thrice a day.
Gastrointestinalni poremećaji kao što su ulcerativni kolitis, Kronova bolest, i hipersekrecija želučane kiseline mogu biti prikladno tretirani kapsulama, pilulama ili tabletama koji sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and gastric acid hypersecretion can be conveniently treated with capsules, pills, or tablets containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the subject application compound. , or its pharmaceutically acceptable salts, administered once, twice, or three times a day.
Infektivne bolesti kao što su bakterijski, gljivično ili virusno izazvane sepse ili septički šok, endotoksički šok (i srodna stanja kao što su laminitis i grčevi u konje), i septički šok mogu biti prikladno tretirani kapsulama, pilulama ili tabletama koji sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg) 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and equine colic), and septic shock can be conveniently treated with capsules, pills or tablets containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg) 300mg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.
Neurološki poremećaja kao što su ozljede leđne moždine, povrede glave, neurogene upale, bolovi, i reperfuzijske povreda mozga mogu biti prikladno tretirane kapsulama, pilulama ili tabletama, koje sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davane jednom, dvaput, ili triput dnevno. Neurological disorders such as spinal cord injuries, head injuries, neurogenic inflammation, pain, and brain reperfusion injuries can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500 mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.
Upalni poremećaji, kao što su psorijatrijski artritis, reumatski artritis, ankilozni spondilitis, osteoartritis, upala i citofcin-posredovana kronična degeneracija tkiva mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koji sadržavaju 1mg, 5mg, 25mg, 50mg; 100mg, 200mg, 30Gmg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Inflammatory disorders, such as psoriatic arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytoficin-mediated chronic tissue degeneration can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg; 100mg, 200mg, 30Gmg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.
Alergijski poremećaji kao što su alergijski rinitis, alergijski konjuktivitis, i eozinofilni granulom, mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koje sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma can be conveniently treated with capsules, pills, or tablets containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the subject compound. application, or its pharmaceutically acceptable salts, administered once, twice, or three times a day.
Psihijatrijski poremećaji kao što su depresija, oštećenje memorije, i monopolarna depresija mogu biti prikladno tretirani kapsulama, pilulama ili tabletama koje sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Psychiatric disorders such as depression, memory impairment, and monopolar depression may be conveniently treated with capsules, pills, or tablets containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of the active ingredient of the subject application compound, or its pharmaceutically acceptable salts, administered once, twice, or thrice daily.
Neurodegenerativni poremećaji kao što su Parkinson-ova bolest, Alzheimero-va bolest, akutna i kronična multipla skleroza mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koje sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoj a predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg. of the active ingredient of compound a of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.
Dermatološki poremećaji kao Što su psoriaza i benigne ili maligne proliferativne kožne bolesti, atopički dermatitis, i urticaria mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koje sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Dermatological disorders such as psoriasis and benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria can be appropriately treated with capsules, pills, or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of active an ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.
Onkološke bolesti kao što su rak, rast tumora i kancerogena invazija normalnanog tkiva mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koje sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mgs 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissue can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mgs 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salts, administered once, twice, or thrice daily.
Metabolički poremećaji kao što su diabetes insipidus, mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koje sadržavaju 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Metabolic disorders such as diabetes insipidus can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt. , given once, twice, or three times a day.
Koštani poremećaji kao što su osteoporoza, kardiovaskularni poremećaji kao što su arterijska restenoza, arteroskleroza, reperfuzijskih povreda miokarda, i terapijski poremećaji kao što su kronični glomerulonefritis, vernalni konjuktivitis, odbacivanje transplantata i implantata, i kaheksija mogu biti prikladno tretirani kapsulama, pilulama ili tabletama, koje sadržavaju 1 mg, 5mg, 25mg, 50mg, l 00mg, 200mg, 300mg, 400mg, ili 500mg aktivnog sastojka od spoja predmetne prijave, ili njegove farmaceutski prihvatljive soli, davani jednom, dvaput, ili triput dnevno. Bone disorders such as osteoporosis, cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and therapeutic disorders such as chronic glomerulonephritis, vernal conjunctivitis, graft and implant rejection, and cachexia may be appropriately treated with capsules, pills, or tablets. containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.
Kratice koje se ovdje koriste prikazane su u tablicama i imaju slijedeća značenja. Kratice koje nisu prikazane dolje imaju značenja koja su najčešće korištena, ukoliko izrijekom nije naznačeno drugačije. The abbreviations used here are shown in the tables and have the following meanings. Abbreviations not shown below have meanings that are most commonly used, unless otherwise indicated by the verb.
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KRATICE ALKIL GRUPE ALKYL GROUP ABBREVIATIONS
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TESTOVI KOJI DOKAZUJU BIOLOŠKU AKTIVNOST TESTS THAT PROVE BIOLOGICAL ACTIVITY
LPS IFMLP-INDUCIRANI TNF-α ILTB4 TESTOVI U LJUDSKOJ PUNOJ KRVI LPS IFMLP-INDUCED TNF-α ILTB4 ASSAYS IN HUMAN WHOLE BLOOD
Puna krv omogućava proteinima i sanicama bogatu podlogu prikladnu za proučavanje biokemijske efikasnosti anti-upalnih spojeva, kao što su PDE4-selektivni inhibitori. Normalna ne-stimulirana ljudska krv ne sadrži detektabilne razine TNF-α i LTB4, Nakon stimulacije sa LPS, aktivirani monociti ekspresiraju i luče TNF-α do 8 sati a razina u plazmi ostaje stabilna 24 sata. Objavljene studije prikazuju da se inhibicija TNF-α povećavanjem intrastaničnog cAMP putem PDE4 inhibicije i/ili pojačane aktivnosti adenilil ciklaze odvija na razini transkripcije. LTB4 sinteza je također osjetljiva na razine intrastaničnog cAMP i može biti potpuno inhibirana PDE4-selektivnim inhibitorima. Kako se malo LTB4 proizvede tijekom 24 satne LPS stimulacije pune krvi, potrebna je dodatna LPS stimulacija pune ljudske krvi koja je izazvana fMLP, da bi aktivirani neutrofili sintetizirali LTB4. Stoga, koristeći isti uzorak krvi moguće je procijeniti snagu spoja na dva surogatna markera PDE4 aktivnosti u punoj krvi sljedećim postupkom. Whole blood provides a protein- and cell-rich medium suitable for studying the biochemical efficacy of anti-inflammatory compounds, such as PDE4-selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-α and LTB4. After stimulation with LPS, activated monocytes express and secrete TNF-α for up to 8 hours and the plasma level remains stable for 24 hours. Published studies show that inhibition of TNF-α by increasing intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity takes place at the transcriptional level. LTB4 synthesis is also sensitive to intracellular cAMP levels and can be completely inhibited by PDE4-selective inhibitors. As little LTB4 is produced during 24 h LPS stimulation of whole blood, additional LPS stimulation of fMLP-induced human whole blood is required for activated neutrophils to synthesize LTB4. Therefore, using the same blood sample it is possible to evaluate the potency of the compound on two surrogate markers of PDE4 activity in whole blood by the following procedure.
Svježa krv je sakupljena u hepariniziranim epruvetama venepunkcijom zdravih ljudi dobrovoljaca (muškaraca i žena). Ovi subjekti nisu imali vidljiva upalna stanja i nisu uzimala NSAID najmanje 4 dana prije sakupljanja krvi. 500μL alikvota krvi je pre-inkubirano sa ili 2μL nosača (DMSO) ili 2μL testnog spoja pri raznim koncentracijama, tijekom 15 minuta na 37°C. Ovo je praćeno dodavanjem 10μL nosača (PBS) kao slijepe ili 10μL LPS (1μg/mL konačna koncentracija, #F-2630 (Sigma Chemical Co., St. Lom's, MO) od E. coli, serotip 0111 :B4; razrijeđen u 0.1% w/v BSA (u PBS)). Nakon 24 sata inkubacije na 37°C, 10μL PBS (slijepa) ili 10μL LPS (1μg/mL konačna koncentracija) je dodano u krv i inkubirano 30 minuta na 37°C. Krv je zatim pobuđena sa 10μL PBS (slijepa) ili 10μL fMLP (1μM konačna koncentracija, #F-3506 (Sigma); razrijeđen u 1% w/v BSA (u PBS)) tijekom 15 minuta na 37°C. Uzorci krvi su centrifugirani na 1500xg10 minuta na 4°C, da se dobije plazma. 50μL alikvota plazme je miješano sa 200μL metanola, da bi se istaložili proteini, te su centrifugirani kao gore. Supematant je testiran za LTB4 koristeći imunoenzimski test kit (#520111 Cayman Chemical Co., Ann Arbor, MI) po postupku proizvođača. TNF-α je testiran u razrijeđenoj plazmi (u PBS) koristeći ELISA kit (Cistron Biotechnologv, Pine Brook, NJ) po postupku proizvođača. IC50 vrijednosti bi trebali biti manje od oko 5μM, po mogućnosti manje od oko 2.5μM. IC50 vrijednosti u Primjerima l do 33 varirale su od 0.01μM do 2,4μM. Fresh blood was collected in heparinized tubes by venipuncture of healthy human volunteers (men and women). These subjects had no visible inflammatory conditions and had not taken NSAIDs for at least 4 days before blood collection. A 500μL aliquot of blood was pre-incubated with either 2μL of vehicle (DMSO) or 2μL of test compound at various concentrations, for 15 minutes at 37°C. This was followed by the addition of 10 μL of vehicle (PBS) as a blank or 10 μL of LPS (1 μg/mL final concentration, #F-2630 (Sigma Chemical Co., St. Lom's, MO)) from E. coli, serotype 0111 :B4; diluted in 0.1 % w/v BSA (in PBS)). After 24 hours of incubation at 37°C, 10μL of PBS (blank) or 10μL of LPS (1μg/mL final concentration) was added to the blood and incubated for 30 minutes at 37°C. Blood was then stimulated with 10μL PBS (blank) or 10μL fMLP (1μM final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37°C. Blood samples were centrifuged at 1500xg for 10 minutes at 4°C to obtain plasma. A 50μL aliquot of plasma was mixed with 200μL of methanol to precipitate the proteins and centrifuged as above. The supernatant was tested for LTB4 using an enzyme-linked immunosorbent assay kit (#520111 Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer's procedure. TNF-α was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, NJ) according to the manufacturer's procedure. IC50 values should be less than about 5μM, preferably less than about 2.5μM. IC50 values in Examples 1 to 33 varied from 0.01 μM to 2.4 μM.
ANTI-ALERGIJSKA AKTIVNOST IN VIVO ANTI-ALLERGIC ACTIVITY IN VIVO
Spojevi izuma testirani su za djelovanje na IgE-posredovane alergijske upale pluća, izazvane inhalacijom antigena, senzibiliziranog zamorca. Zamorca su senzibilizirali na ovalbumin pod blagom imunosupresijom, izazvanom ciklofosfamidom, intraperitonealnom injekcijom antigena u kombinaciji sa aluminij hidroksidom i vakcinom pertusisa. Velike doze antigena su davane dva i četiri tjedna kasnije. Nakon šest tjedana, životinje su pobuđene ovalbuminom u obliku aerosola, dok su bile zaštićene intraperitonalno davanim anti-histaminskim agensom (mepiramin). Nakon daljnjih 48h, napravljeno je bronhialnno alveolarno ispiranje (BAL) i izmjeren je broj eozinofila i leukocita u BAL fluidu. Također su uklonjena pluća za histološko ispitivanje upalnih oštećenja. Davanje spojeva iz Primjera (0.001-1 0mg/kg i.p. ili p.o.), do tri puta tijekom 48h nakon izazova antigenom dovelo je do značajne redukcije eozinofilije i akumulacije drugih upalnih leukocita. The compounds of the invention were tested for activity on IgE-mediated allergic lung inflammation, induced by antigen inhalation, in a sensitized guinea pig. Guinea pigs were sensitized to ovalbumin under mild immunosuppression, induced by cyclophosphamide, by intraperitoneal injection of antigen in combination with aluminum hydroxide and pertussis vaccine. High doses of antigen were administered two and four weeks later. After six weeks, the animals were stimulated with ovalbumin in aerosol form, while they were protected with an intraperitoneally administered anti-histaminic agent (mepyramine). After a further 48 hours, bronchial alveolar lavage (BAL) was performed and the number of eosinophils and leukocytes in the BAL fluid was measured. Lungs were also removed for histological examination of inflammatory damage. Administration of the compounds from the Example (0.001-10mg/kg i.p. or p.o.), up to three times during 48h after antigen challenge, led to a significant reduction of eosinophilia and accumulation of other inflammatory leukocytes.
SPA BAZIRANA PDE AKTIVNOST PROTOKOL TESTA SPA BASED PDE ACTIVITY TEST PROTOCOL
Spojevi koji inhibiraju hidrolizu cAMP u AMP pomoću tip-FV cAMP-specifičnim fosfodiesteraza su praćeni u pločici s 96-jažica kako slijedi: Compounds that inhibit the hydrolysis of cAMP to AMP by type-FV cAMP-specific phosphodiesterases were screened in a 96-well plate as follows:
U pločicu s 96 jažica na 30°C dodan je testni spoj (otopljen u 2μL DMSO), 188μL supstrat pufera, koji sadrži [2,8-3H] adenozin 3',5'-ciklički fosfat (cAMP, 100nM do 50μM), 10mM MgCl2, 1mM EDTA, 50mM Tris, pH 7.5. Test compound (dissolved in 2μL DMSO), 188μL substrate buffer, containing [2,8-3H] adenosine 3',5'-cyclic phosphate (cAMP, 100nM to 50μM), was added to a 96-well plate at 30°C. 10 mM MgCl2, 1 mM EDTA, 50 mM Tris, pH 7.5.
Reakcija je inicirana dodavanjem ljudske rekombinantne PDE4 (količina je kontrolirana tako da -10% je produkta pripravljeno u 10 min.), Reakcija je zaustavljena nakon 10 min.dodavanjem 1 mg PDE-SPA kuglica (Amersham Pharmacia Biotech, Inc., Piscataway, NJ),Nastali AMP produkt je kvantificiran na Wallace Microbeta® brojaču za pločice (EG&G Wallace Co., Gaithersburg, MD). Signal u odsustvu enzima je definiran kao pozadina. 100% aktivnost je definirana kao signal detektiran u nazočnosti enzima i DMSO sa oduzetom pozadinom. Prema tome je izračunat postotak inhibicije. IC50 vrijednost je aproksimirana sa ne-lineamom regresijom, koristeći standardnu jednadžbu 4-parametra/multipla vezna mjesta titracija na deset točaka. The reaction was initiated by the addition of human recombinant PDE4 (the amount was controlled so that -10% of the product was prepared in 10 min.), the reaction was stopped after 10 min. by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, NJ ), the resulting AMP product was quantified on a Wallace Microbeta® plate counter (EG&G Wallace Co., Gaithersburg, MD). The signal in the absence of enzyme was defined as background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with background subtracted. Accordingly, the percentage of inhibition was calculated. The IC50 value was approximated with non-linear regression, using a standard 4-parameter/multiple binding site ten-point titration equation.
IC50 vrijednosti PRIMJERA 1 do 33 su određeni sa 100nM cAMP koristeći pročišćeni GST fuzijski protein ljudske rekombinantne fosfodiesteraze IVa (met-248) proizveden od baculovirusa/Sf-9 sistemom ekspresije. IC50 vrijednosti bi trebale biti manje od oko 1000nM, po mogućnosti manje od oko 250nM, i štoviše po mogućnosti manje od oko 100nM. IC50 vrijednosti PRIMJERA 1 do 33 varirale su od 0.1nMdo90.0nM. The IC 50 values of EXAMPLES 1 through 33 were determined with 100 nM cAMP using a purified GST fusion protein of human recombinant phosphodiesterase IVa (met-248) produced by the baculovirus/Sf-9 expression system. IC50 values should be less than about 1000nM, preferably less than about 250nM, and even more preferably less than about 100nM. The IC50 values of EXAMPLES 1 through 33 varied from 0.1 nM to 90.0 nM.
Primjeri koji slijede su namijenjeni kao ilustracija izvjesnih poželjnih implementacije izuma i nikakvo ograničenje obima izuma nije implicirano. The following examples are intended to illustrate certain preferred implementations of the invention and no limitation on the scope of the invention is implied.
Ukoliko izrijekom nije naznačeno drugačije, eksperimentalni postupci su pripravljeni pod sljedećim uvjetima. Sve operacije su izvršene na sobnoj ili ambientalnoj temperaturi - koja je u opsegu 18-25°C. Otparavanje otapala je izvršeno koristeći rotirajući evaporator pod reduciranim tlakom (600-4000paskala: 4.5-30mm Hg) sa temperaturom kupelji od do 60°C. Tijek reakcija je praćen kromatografijom tankog sloja (TLC) i vremena reakcije su data samo kao ilustracija. Točke tališta su neispravljene i "d" označava dekompoziciju. Točke tališta su one dobivene za materijale pripravljene kako je opisano, Polimorfizam može rezultirati izolacijom materijala sa različitim točkama tališta u nekim pripravama. Struktura i čistoća svih konačnih produkta su osigurani najmanje jednom od sljedećih tehnika: TLC, spektrometrija masa, nuklearna magnetska rezonanca (NMR) spektrometrija ili mikroanalitičkim podacima. Prinosi koji su dati su samo radi ilustracije. NMR podaci dati su u obliku delta (δ) vrijednosti velikih dijagnostičkih protona, dati u dijelovima po milijunu (ppm) u odnosu na tetrametilsilan (TMS) kao interni standard, određeni na 300 MHz, 400 MHz ili 500 MHz koristeći indicirano otapalo. Konvencionalne kratice korištene za oblik signala su: s, singlet; d. dublet; t. triplet; m. multiplet; br. široko; itd. Dodatno, "Ar" označava aromatski signal. Kemijski simboli imaju uobičajena značenja; sljedeća kratice su također korištene: v (volumen), w (težina), b.p. (točka vrelišta), m.p. (točka tališta), L (Htra(i)),mL (millilitra), g (gram(i)), mg (miligram(i)), mol (moli), mmol (milimoli), eq (ekvivalent(i)). Unless otherwise indicated, the experimental procedures were prepared under the following conditions. All operations were performed at room or ambient temperature - which is in the range of 18-25°C. Solvent evaporation was performed using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60°C. The course of the reactions was monitored by thin layer chromatography (TLC) and the reaction times are given as an illustration only. Melting points are uncorrected and "d" indicates decomposition. Melting points are those obtained for materials prepared as described. Polymorphism may result in the isolation of materials with different melting points in some preparations. The structure and purity of all final products is ensured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. The yields given are for illustration purposes only. NMR data are given as delta (δ) values of large diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz, 400 MHz, or 500 MHz using the indicated solvent. Conventional abbreviations used for the signal shape are: s, singlet; d. doublet; t. triplet; m. multiplet; no. wide; etc. Additionally, "Ar" indicates an aromatic signal. Chemical symbols have the usual meanings; the following abbreviations are also used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (Htra(s)),mL (milliliters), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), eq (equivalent(s) ).
Metode Sinteze Methods of Synthesis
Spojevi predmetnog izuma mogu biti pripravljeni po sljedećim metodama, Supstituenti su isti kao u Formuli I, osim gdje je definirano drugačije. The compounds of the subject invention can be prepared by the following methods, Substituents are the same as in Formula I, except where defined otherwise.
U prvoj metodi opisanoj dolje u Shemi l, prikladno supstituirani derivat etil 2-kloronikotinoil acetata formule II je reagira sa 1.5 ekvivalenta trietil ortoformata i 5 ekvivalenta octenog anhidrida na 130°C, i nakon uklanjanja nestabilnih komponenti sirovi 2-kloronikotinoil akrilat formule III odmah reagira sa l.2 ekvivalenta prikladno supstituiranog haloaril amina, formule IV, kao što je, na primjer 3-bromoanilin, u halogenirano ugljikovodično otapalo, kao Što je metilen klorid, na temperaturi od 0°C do sobne temperature. Nakon prikladnog vremena reakcije, koje varira od 2 do 24 sati, rezultirajući 3-arilamino akrilat formule V je dobiven otparavanjem otapala i može biti nadalje pročišćen kromatografijom na silika gelu ili kristalizacijom iz prikladnog otapala. Spoj formule V može alternativno biti korišten bez daljnjeg pročišćavanja u sljedećem koraku. Ciklizacijom spoja formule V na l-haloaril-1,4-dihidro[1,8]naftiridin-4-on karboksilat formule VI je postignuta tretiranjem malim suviškom jake baze, kao stoj e alkalni metal hidrid, na primjer natrij hidrid, u prikladnom otapalu kao što je tetrahidrofuran, na početnoj temperaturi od 0°C zagrijavanjem do sobne temperature, po potrebi, da se dovrši postupak. Produkt formule VI je izoliran u sirovom obliku razrjeđivanjem sa velikim volumenom vode, praćeno filtracijom ili ekstrakcijom sa prikladnim organskim otapalom, kao stoje dietil eter, etil acetat, ili halogenirano ugljikovodično otapalo, kao što je kloroform ili metilen klorid. Produkt može biti nadalje pročišćen kromatografijom na silika gelu, kristalizacijom ili produljenim miješanjem u prikladnom otapalu praćeno filtracijom. In the first method described below in Scheme 1, an appropriately substituted ethyl 2-chloronicotinoyl acetate derivative of formula II is reacted with 1.5 equivalents of triethyl orthoformate and 5 equivalents of acetic anhydride at 130°C, and after removal of the unstable components the crude 2-chloronicotinoyl acrylate of formula III is immediately reacted with 1.2 equivalents of a suitably substituted haloaryl amine of formula IV, such as, for example, 3-bromoaniline, in a halogenated hydrocarbon solvent, such as methylene chloride, at a temperature of 0°C to room temperature. After a suitable reaction time, varying from 2 to 24 hours, the resulting 3-arylamino acrylate of formula V is obtained by evaporation of the solvent and can be further purified by silica gel chromatography or crystallization from a suitable solvent. The compound of formula V may alternatively be used without further purification in the next step. Cyclization of the compound of formula V to l-haloaryl-1,4-dihydro[1,8]naphthyridin-4-one carboxylate of formula VI was achieved by treatment with a small excess of a strong base, such as an alkali metal hydride, for example sodium hydride, in a suitable solvent such as tetrahydrofuran, at an initial temperature of 0°C by warming to room temperature, if necessary, to complete the process. The product of formula VI is isolated in crude form by dilution with a large volume of water, followed by filtration or extraction with a suitable organic solvent, such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent, such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization or prolonged stirring in a suitable solvent followed by filtration.
Ester produkt formule VI tako dobiven može biti hidroliziran na odgovarajući derivat karboksilne kiseline pod baznim uvjetima, koristeći vodenu otopinu alkalne baze, kao stoje alkalni karbonat ili poželjno natrij ili kalijev hidroksid, sa organskim su-otapalom, kao što su tetrahidrofuran ili primarni, sekundarni ili tercijarni alkanol, kao što su metanol ili etanol, ili njihove kombinacije na temperaturama koje variraju od sobne do temperature refluksa, u prikladnom vremenu. Rezultirajuća karboksilna kiselina je izolirana u sirovom obliku, nakon zakiseljavanja, koristeći vodenu otopinu neorganske kiseline, kao što su klorovodična, sumporna ili slična kiselina, i filtracijom ili ekstrakcijom sa prikladnim organskim otapalom kao što su dietil eter, etil acetat, ili halogenirano ugljikovodično otapalo, kao što su kloroform ili metilen klorid. Produkt može biti nadalje pročišćen kromatografijom na silika gelu, kristalizacijom ili produljenim miješanjem u prikladnom otapalu, praćeno filtracijom. Karboksilna kiselina je zatim transformirana u prikladan primarni, sekundarni ili tercijarni amid analog formule VII, bilo kojim općim postupkom poznatim organskim kemičarima, poželjno putem početne transformacije u mješoviti anhidrid tretiranjem malim suviškom, obično 1.25 ekvivalenta, prikladnog alkil kloroformata, kao što su etil ili izobutil kloroformat, u nazočnosti većeg suviška, obično 2.5 ekvivalenta, tercijarnog organskog amina kao što je trietilamin ili N,N-diizopropiletilamin, u organskom otapalu kao što je tetrahidrofuran na niskoj temperaturi, poželjno 0°C tijekom 30 minuta do 3 sata. Alternativno, kiselina može biti transformirana u kiseli klorid kroz djelovanje, na primjer, tionil klorida. Suvišak, obično 5 ili više ekvivalenta, prikladnog primarnog ili sekundarnog amina ili vodene otopine amonij hidroksida je dodano i reakcija je ostavljena na temperaturi koja varira od 0°C do sobne temperature, u prikladnom trajanju, obično 1-24 sati. Željeni amid formule VII je izoliran u sirovom obliku precipitacijom sa vodom i filtracijom ili ekstrakcijom sa prikladnim organskim otapalom kao što su dietil eter, etil acetat, ili halogenirano ugljikovodično otapalo, kao što su kloroform ili metilen klorid. Produkt može biti nadalje pročišćen kromatografijom na silika gelu, kristalizacijom ili produljenim miješanjem u prikladnom otapalu, praćeno filtracijom. Alternativno amid formule VII može biti dobiven od kiseline i amina putem prikladnog reagensa kupliranja, kao Sto je karbonildiimidazol (CDI). U slučajevima gdje je amid dio 2,6-dikloropiridin-4-il koristi se drugačiji postupak u kojem se anion 4-amino-3,5-dikloropiridina generira na niskoj temperaturi, poželjno na 0°C koristeći jaki alkalni hidrid, kao što je natrij liidrid u otapalu kao stoje tetrahidrofuran, i reakcijom s kiselm kloridom karboksilne kiseline (iz hidrolize estera formule VI) generirano prikladnim poznatim postupkom, obično djelovanjem oksalil klorida aktiviranog katalitičkom količinom N,N-dimetilformamida u otapalu kao stoje tetrahidrofuran. The ester product of formula VI thus obtained can be hydrolyzed to the corresponding carboxylic acid derivative under basic conditions, using an aqueous solution of an alkaline base, such as alkaline carbonate or preferably sodium or potassium hydroxide, with an organic co-solvent, such as tetrahydrofuran or primary, secondary or tertiary alkanol, such as methanol or ethanol, or combinations thereof at temperatures ranging from room temperature to reflux temperature, for a suitable time. The resulting carboxylic acid is isolated in crude form, after acidification, using an aqueous solution of an inorganic acid, such as hydrochloric, sulfuric or similar acid, and by filtration or extraction with a suitable organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent, such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization or prolonged stirring in a suitable solvent, followed by filtration. The carboxylic acid is then transformed into a suitable primary, secondary or tertiary amide analogue of formula VII by any general procedure known to organic chemists, preferably by initial transformation to the mixed anhydride by treatment with a small excess, usually 1.25 equivalents, of a suitable alkyl chloroformate, such as ethyl or isobutyl chloroformate, in the presence of a large excess, usually 2.5 equivalents, of a tertiary organic amine such as triethylamine or N,N-diisopropylethylamine, in an organic solvent such as tetrahydrofuran at low temperature, preferably 0°C for 30 minutes to 3 hours. Alternatively, the acid may be transformed into the acid chloride through the action of, for example, thionyl chloride. An excess, usually 5 or more equivalents, of a suitable primary or secondary amine or aqueous ammonium hydroxide solution is added and the reaction allowed to take place at a temperature varying from 0°C to room temperature for a suitable time, usually 1-24 hours. The desired amide of formula VII is isolated in crude form by precipitation with water and filtration or extraction with a suitable organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization or prolonged stirring in a suitable solvent, followed by filtration. Alternatively, the amide of formula VII can be prepared from an acid and an amine via a suitable coupling reagent, such as carbonyldiimidazole (CDI). In cases where the amide moiety is 2,6-dichloropyridin-4-yl, a different procedure is used in which the 4-amino-3,5-dichloropyridine anion is generated at low temperature, preferably 0°C, using a strong alkaline hydride, such as sodium hydride in a solvent such as tetrahydrofuran, and by reaction with the acid chloride of a carboxylic acid (from the hydrolysis of an ester of formula VI) generated by a suitable known process, usually by the action of oxalyl chloride activated by a catalytic amount of N,N-dimethylformamide in a solvent such as tetrahydrofuran.
Za sintezu spojeva formule I, amid spoja formule VII reagira sa prikladno supstituiranim acetilenom formule VIII pod katalizom tranzicijskog metala kao što su bis(trifenilfosfin)paladij (H) klorid ili [1,1'-bis(difenilfosfmo)ferocen]dikloropaladij(H) u prikladnom otapalu kao što su THF ili DMF, u nazočnosti trietilamina i bakrene soli kao što je bakar jodid, na temperaturi koja varira od sobne do temperature refluksa za prikladan vremenski period. Alternativno, ester spoja formule VI može reagirati na isti način da se dobije ester spoja formule IX, koji je podvrgnut hidrolizi i amidacijskim procesima, opisanim gore, što vodi do spoja formule I. For the synthesis of compounds of formula I, the amide of a compound of formula VII is reacted with an appropriately substituted acetylene of formula VIII under transition metal catalysis such as bis(triphenylphosphine)palladium(H) chloride or [1,1'-bis(diphenylphosphmo)ferrocene]dichloropalladium(H) in a suitable solvent such as THF or DMF, in the presence of triethylamine and a copper salt such as copper iodide, at a temperature varying from room temperature to reflux for a suitable period of time. Alternatively, an ester of a compound of formula VI may be reacted in the same manner to give an ester of a compound of formula IX, which is subjected to the hydrolysis and amidation processes described above, leading to a compound of formula I.
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U drugom pristupu sintezi spojeva formule I, opisanoj dolje u Shemi 2, amid formule VII reagira sa trimetilsililacetilenom pod katalizom tranzicijskih metala kao što su bis(trifenilfosfin)paladij (II) klorid ili [1,1'-bis(difenilfosfino)ferocen]dikloropaladij(II) u prikladnom otapalu, kao Što su THF ili DMF, u nazočnosti trietilamina i bakrene soli, kao što je bakreni jodid, na temperaturi koja varira od sobne temperature do refluksa, tijekom prikladnog vremenskog perioda. Rezultirajući spoj je oslobođen TMS zaštitne grupe pod djelovanjem vodene otopine alkalnog hidroksida, kao što su natrij ili kalij hidroksid u nazočnosti organskog su-otapala kao što je metanol, ili alternativno tretiranjem sa izvorom fluorida, kao stoje tetrabutilamonij fluorid u THF otopini, da se dobije acetilen derivat formule X. In another approach to the synthesis of compounds of formula I, described below in Scheme 2, an amide of formula VII is reacted with trimethylsilylacetylene catalyzed by transition metals such as bis(triphenylphosphine)palladium(II) chloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) in a suitable solvent, such as THF or DMF, in the presence of triethylamine and a copper salt, such as copper iodide, at a temperature varying from room temperature to reflux, for a suitable period of time. The resulting compound is deprotected by the TMS protecting group under the action of an aqueous alkaline hydroxide solution, such as sodium or potassium hydroxide in the presence of an organic co-solvent such as methanol, or alternatively by treatment with a fluoride source, such as tetrabutylammonium fluoride in THF solution, to give an acetylene derivative of formula X.
Takav spoj reagira sa prikladnim alkil ili aril ili heteroaril halidom formule XI pod katalizom tranzicijskih metala kao što su bis(trifenilfosfin)paladij (H) klorid ili [1,1'-bis(difenilfosfino)ferocen]dikloropaladij(II) u prikladnom otapalu kao Sto su THF ili DMF, u nazočnosti trietilamina i bakrene soli, kao što je bakreni jodid, na temperaturi koja varira od sobne temperature do refluksa, tijekom prikladnog vremenskog perioda, da se dobije spoj formule I. Alternativno, ester spoja formule VI može biti procesiran na isti način, da se dobije ester spoja formule IX, koji je podvrgnut hidrolizi i amidacijskom procesu, opisanom gore, što vodi do spoja formule I. Such a compound is reacted with a suitable alkyl or aryl or heteroaryl halide of formula XI under the catalysis of transition metals such as bis(triphenylphosphine)palladium(H) chloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a suitable solvent as which are THF or DMF, in the presence of triethylamine and a copper salt, such as copper iodide, at a temperature varying from room temperature to reflux, for a suitable period of time, to give a compound of formula I. Alternatively, the ester of a compound of formula VI may be processed in the same way, to obtain the ester of the compound of formula IX, which is subjected to the hydrolysis and amidation process, described above, leading to the compound of formula I.
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U alternativnom pristupu acetilenski esteri formule IX ili XII (gdje je R8 = H), opisani u Shemi 3, prikladno supstituiran 2-kloronikotinoil klorid formule XIII reagira sa 3-dialkilaminoakrilatom, na primjer etil 3-dimetilaminoakrilat, u nazočnosti tercijarnog amina, kao što je trietilamin u otapalu kao što je toluen, na prikladnoj temperaturi, da se dobije 3-dialkilamino akrilat formule XIV. Takva supstanca reagira sa prikladno supstituiranim 3-aminofenilacetilen derivatom formule XV, u otapalu kao stoje DMF ili acetonitril, u nazočnosti neorganske baze, kao stoje kalijev karbonat, na prikladnoj temperaturi, da se dobije acetilenski ester formule IX ili XII (gdje je R8 = H). In an alternative approach, the acetylenic esters of formula IX or XII (where R 8 = H) described in Scheme 3 are reacted with a suitably substituted 2-chloronicotinoyl chloride of formula XIII with a 3-dialkylaminoacrylate, for example ethyl 3-dimethylaminoacrylate, in the presence of a tertiary amine, such as is triethylamine in a solvent such as toluene at a suitable temperature to give the 3-dialkylamino acrylate of formula XIV. Such a substance is reacted with an appropriately substituted 3-aminophenylacetylene derivative of formula XV, in a solvent such as DMF or acetonitrile, in the presence of an inorganic base, such as potassium carbonate, at a suitable temperature, to give an acetylenic ester of formula IX or XII (where R8 = H ).
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Većina acetilenskih reagensa formule VIII korištenih u ovom izumu su iz komercijalnih izvora. Tamo gdje je potrebno, prikladno supstituirani acetileni formule VIII su sintetizirani kako je opisano u Shemi 4, po mogućnosti od odgovarajućih halida (XI) početnom kondenzacijom sa trimetilsililacetilenom, pod katalizom tranzicijskih metala, praćeno uklanjanjem TMS grupe, kako je gore opisano u Shemi 2 priprave spojeva tipa X ili XII. Kada je supstituent R8 acetilen sekundarni ili tercijarni alkohol, anion trimetilsililacetilena je generiran na niskoj temperaturi, koristeći alkillitijsku bazu kao što je n-butillitij, i može reagirati sa prikladno supstituiranim aldehidom ili ketonom, da se dobije željeni reagens formule VIII. Most of the acetylenic reagents of formula VIII used in this invention are from commercial sources. Where necessary, suitably substituted acetylenes of formula VIII are synthesized as described in Scheme 4, preferably from the corresponding halides (XI) by initial condensation with trimethylsilylacetylene, under transition metal catalysis, followed by removal of the TMS group, as described in Preparation Scheme 2 above compounds of type X or XII. When the R8 substituent is an acetylene secondary or tertiary alcohol, the trimethylsilylacetylene anion is generated at low temperature, using an alkyllithium base such as n-butyllithium, and can be reacted with an appropriately substituted aldehyde or ketone to give the desired reagent of formula VIII.
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Sljedeći su primjeri sinteze arila i heteroaril halida, koji odgovaraju spojevima formule XI koji nose sekundarni ili tercijarni alkohol kao supstituent. Za piridin derivat (Shema 5), halogen-supstituirani piridil karboksilat formule XVI može reagirati sa organometalom kao što su Grignard reagensi, da se dobije tercijarni alkohol formule XVII. Alternativno, dibromopiridin supstrat formule XVIII može biti monometaliran koristeći alkillitijsku vrstu, kao što je n-butillitij, praćeno dodavanjem aldehida ili ketona, da se dobije spoj formule XVII. The following are examples of the synthesis of aryl and heteroaryl halides, corresponding to compounds of formula XI bearing a secondary or tertiary alcohol substituent. For the pyridine derivative (Scheme 5), the halogen-substituted pyridyl carboxylate of formula XVI can be reacted with organometallics such as Grignard reagents to give the tertiary alcohol of formula XVII. Alternatively, the dibromopyridine substrate of formula XVIII may be monometalated using an alkyllithium species, such as n-butyllithium, followed by addition of an aldehyde or ketone, to give a compound of formula XVII.
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Tiofen derivat formule XX rezultira iz reakcije halogen supstituiranog tiofen aldehida ili ketona formule XIX (Shema 6) sa organometalnom vrstom kao što je Grignard reagens. A thiophene derivative of formula XX results from the reaction of a halogen-substituted thiophene aldehyde or ketone of formula XIX (Scheme 6) with an organometallic species such as a Grignard reagent.
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Za sintezu tiazol derivata formule XXII, opisanu u Shemi 7, početna metalizacija tiazola, koristeći alkillitij kao što je n-butillitij, praćeno dodavanjem aldehida ili ketona daje 2-tiazolil sekundarni ili tercijarni alkohol koji je odgovarajuće zaštićen, na primjer kao SEM eter formule XXI. Daljnja brominacija vodi do uvođenja bromo atoma na 5-poziciji sa istovremenim uklanjanjem zaštitne grupe, rezultirajući spojem formule XXII. For the synthesis of thiazole derivatives of formula XXII, described in Scheme 7, initial metalation of the thiazole, using an alkyllithium such as n-butyllithium, followed by addition of an aldehyde or ketone gives the 2-thiazolyl secondary or tertiary alcohol that is suitably protected, for example as the SEM ether of formula XXI . Further bromination leads to the introduction of a bromo atom at the 5-position with simultaneous removal of the protecting group, resulting in the compound of formula XXII.
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Tamo gdje je potrebno, piridin derivati mogu biti oksidirani na odgovarajuće N-okside, koristeći dobro poznate reagense, kao što su m-kloroperoksibenzojeva kiselina ili magnezij monoperoksiftalat. Where necessary, the pyridine derivatives can be oxidized to the corresponding N-oxides, using well-known reagents, such as m-chloroperoxybenzoic acid or magnesium monoperoxyphthalate.
PRIMJERI EXAMPLES
S referencom na formulu dolje, Primjeri 1-33 su prikazani u TABELI 1 dolje. With reference to the formula below, Examples 1-33 are shown in TABLE 1 below.
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TABELA 1 TABLE 1
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S referencom na formulu dolje, Primjeri 1-33 su prikazani u TABELI 2 dolje. With reference to the formula below, Examples 1-33 are shown in TABLE 2 below.
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TABELA 2: TABLE 2:
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PRIMJER 1 EXAMPLE 1
N-izopropil-1-[3-(feniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksaniid N-isopropyl-1-[3-(phenylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxaniide
Korak 1: etil 3-(3-bromoanilino)-2-(2-kloronikotinoil) akrilat. Step 1: Ethyl 3-(3-bromoanilino)-2-(2-chloronicotinoyl) acrylate.
Smjesa etil 2-kloronikotinoil acetata(41,1g, 180.5mmol), trietil ortoformata (40.12g 271mmol) i octenog anhidrida (92.05g, 902.5mmol) je zagrijavana na 130°C tijekom 2.5 sata. Nestabilne komponenti su destilirane i rezultirajući ostatak je otparen dvaput pomoću ksilena. Uljni ostatak je otopljen u metilen kloridu (250mL) i polagano je dodan 3-bromoanilin (37.25g, 216.6mmol). Rezultirajuća otopina je miješana na sobnoj temperaturi tijekom 18 sati, i otapalo otpareno. Rezultirajući sirovi spoj je korišten kao takav u sljedećem koraku. A mixture of ethyl 2-chloronicotinoyl acetate (41.1g, 180.5mmol), triethyl orthoformate (40.12g, 271mmol) and acetic anhydride (92.05g, 902.5mmol) was heated at 130°C for 2.5 hours. Unstable components were distilled off and the resulting residue was evaporated twice using xylene. The oily residue was dissolved in methylene chloride (250 mL) and 3-bromoaniline (37.25 g, 216.6 mmol) was slowly added. The resulting solution was stirred at room temperature for 18 hours, and the solvent was evaporated. The resulting crude compound was used as such in the next step.
Korak 2: etil 1-(3-bromofenil)-1,4-dihidro[1.8]naftiridin-4-on-3-karboksilat. Step 2: Ethyl 1-(3-bromophenyl)-1,4-dihydro[1.8]naphthyridin-4-one-3-carboxylate.
Sirovi spoj iz Koraka 1 je otopljen u tetrahidrofuranu (500mL), otopina je ohlađena do 0°C, i natrij hidrid (kao 60% disperzija u ulju, 9.4g, 235mmol) je dodan u obrocima. Nakon miješanja na 0° tijekom 1 sata, rezultirajuća smjesa je puštena da se zagrije do sobne temperature. Nakon 2 sata, voda (400mL) je dodana u rezultirajuću suspenziju i neotopljena krutina je filtrirana i ispirana vodom. Osušena krutina je miješana u eteru (150mL) na sobnoj temperaturi tijekom 24 sata, te filtrirana da se dobije etil 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilat spoj kao krutina krem boje. The crude compound from Step 1 was dissolved in tetrahydrofuran (500mL), the solution was cooled to 0°C, and sodium hydride (as a 60% dispersion in oil, 9.4g, 235mmol) was added portionwise. After stirring at 0° for 1 hour, the resulting mixture was allowed to warm to room temperature. After 2 hours, water (400 mL) was added to the resulting suspension and the undissolved solid was filtered and washed with water. The dried solid was stirred in ether (150mL) at room temperature for 24 hours, and filtered to give the ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate compound. as a cream-colored solid.
1H NMR (aceton-de) δ 1.32 (t, 3H), 4.29 (q, 2H), 7.54-7.63 (m, 2H), 7.69 (dd, 1H), 7.7S (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, 3H). 1H NMR (acetone-de) δ 1.32 (t, 3H), 4.29 (q, 2H), 7.54-7.63 (m, 2H), 7.69 (dd, 1H), 7.7S (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, 3H).
Korak 3: 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilna kiselina. Step 3: 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid.
Suspenzija etila 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilata iz Koraka 2 (52.5 g, 140.7mmol) u smjesi tetrahidromrana (400mL), metanola (400mL) i 1N vodenog natrij hidroksida (280mL) je zagrijavana na cea 50°C uz miješanje tijekom 20 minuta. Nakon hlađenja, smjesa je razrijeđena vodom (300mL) i 1N vodena HCl (325mL) je dodana. Nakon miješanja od 45 minuta, precipitat je filtriran, dobro ispran vodom i osušen da se dobije 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilna kiselina kao krutina kreni boje. A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 (52.5 g, 140.7 mmol) in a mixture of tetrahydrofuran (400 mL), methanol (400 mL) and 1N aqueous sodium hydroxide (280mL) was heated to 50°C with stirring for 20 minutes. After cooling, the mixture was diluted with water (300 mL) and 1N aqueous HCl (325 mL) was added. After stirring for 45 minutes, the precipitate was filtered off, washed well with water and dried to give 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid as a crimson solid .
1H NMR(aceton-d6) δ 7.65 (t, 1H), 7.76 (m, 2H), 7.84 (d, 1H),7.99(s, 1H), 8.87 (m, 2H), 9.01 (s, 1H). 1H NMR(acetone-d6) δ 7.65 (t, 1H), 7.76 (m, 2H), 7.84 (d, 1H), 7.99 (s, 1H), 8.87 (m, 2H), 9.01 (s, 1H).
Korak 4: N-izopropil-1-(3-bromofenin-1,4-dihidro[1.81naftiridin-4-on-3-karboksamid. Step 4: N-isopropyl-1-(3-bromophenin-1,4-dihydro[1,81-naphthyridin-4-one-3-carboxamide.
U suspenziju 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilne kiseline iz Koraka 3 (26.3g, 76mniol) i trietilamina (23.2g, 230mmol) u tetrahidrofuranu (1000mL) na 0°C, je dodan izobutii kloroformat (l 8.85g, 138mmol). Nakon miješanja na 0°C tijekom 2 sata, izopropilamin (23g, 390mmol) je dodan i smjesa je puštena da se zagrije do sobne temperature, te miješana preko noći. Smjesa je zatim odijeljena između etil acetata i vode, organska faza je osušena i otparena do krutine, koja je miješana u eteru, na sobnoj temperaturi tijekom 3 sata, te filtrirana, da se dobije N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid kao bijela krutina. To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 3 (26.3g, 76mmol) and triethylamine (23.2g, 230mmol) in tetrahydrofuran ( 1000mL) at 0°C, isobutyl chloroformate (l 8.85g, 138mmol) was added. After stirring at 0°C for 2 hours, isopropylamine (23g, 390mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid, which was stirred in ether at room temperature for 3 hours and filtered to give N-isopropyl-1-(3-bromophenyl)- 1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
1H NMR (aceton-d6) δ 1,25 (d, 6H), 4,17 (m, 1H), 7.59-7.63 (m, 2H), 7.70 (d, 1H), 7.80 (d, 1H), 7.94 (s, 1H), 8.73 (m, 1H), 8.78 (d, 1H), 8.85 (s, 1H), 9.61 (br, MH). 1H NMR (acetone-d6) δ 1.25 (d, 6H), 4.17 (m, 1H), 7.59-7.63 (m, 2H), 7.70 (d, 1H), 7.80 (d, 1H), 7.94 (s, 1H), 8.73 (m, 1H), 8.78 (d, 1H), 8.85 (s, 1H), 9.61 (br, MH).
Korak 5:N-izopropil-1-[(3-feniletinil)fenil]-1,4-dihidro[l,81naftiridin-4-on-3-karboksamid. Step 5: N-isopropyl-1-[(3-phenylethynyl)phenyl]-1,4-dihydro[1,81-naphthyridin-4-one-3-carboxamide.
Smjesa amida iz Koraka 4, fenilacetilena (1.9 eq), trietilamina (1.6 eq), trifenilfosfina (0.06 eq) i bis(trifenilfosfm)paladij (II) klorida (0.05 eq) u THF (16mL/mmol) je miješana na sobnoj temperaturi tijekom 20 minuta. Bakar (I) jodid (5 mg/mmol)je dodani smjesa je miješana na refluksu tijekom 18 sati. Nakon hlađenja, smjesa je gažena zasićenom otopinom vodenog amonij klorida i odijeljena između etil acetata i vode. Organske faza je osušena preko magnezij sulfata i sirovi produkt je kromatografiran na silika gelu, eluiran sa 1:9 smjesom etera i metilen klorida, da se dobije krutina, koja je miješana u eteru na sobnoj temperaturi, te filtrirana da se dobije N-izopropil-1-[(3-feniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid spoj, kao krutina. A mixture of the amide from Step 4, phenylacetylene (1.9 eq), triethylamine (1.6 eq), triphenylphosphine (0.06 eq) and bis(triphenylphosphine)palladium(II) chloride (0.05 eq) in THF (16mL/mmol) was stirred at room temperature for 20 minutes. Copper (I) iodide (5 mg/mmol) was added and the mixture was stirred at reflux for 18 hours. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the crude product was chromatographed on silica gel, eluted with a 1:9 mixture of ether and methylene chloride, to give a solid, which was stirred in ether at room temperature and filtered to give N-isopropyl- 1-[(3-phenylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound, as a solid.
1H NMR (aceton-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.42 (m, 3H), 7.56-7.61 (m, 3H), 7.69 (m, 2H), 7.76 (m, 1H), 7.85 (s, 1H), 8.73 (m, 1H), 8.77 (dd, 1H), 8.88 (s, 1H), 9.62 (br, NH). 1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.42 (m, 3H), 7.56-7.61 (m, 3H), 7.69 (m, 2H), 7.76 (m, 1H ), 7.85 (s, 1H), 8.73 (m, 1H), 8.77 (dd, 1H), 8.88 (s, 1H), 9.62 (br, NH).
PRIMJER 2 EXAMPLE 2
N-izopropi1-[3-(2-piridiniIetinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-[3-(2-pyridinyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, mijenjajući 2-etinilpiridin za fenilacetilen, naslovni spoj je dobivena kao smeđa krutina. After applying the procedure of Step 5 of EXAMPLE 1, substituting 2-ethynylpyridine for phenylacetylene, the title compound was obtained as a brown solid.
1H NMR(aceton-d6) δ 1.25 (d, 6H), 4.18 (m, 1H), 7.38 (m, 1H), 7.59-7.64 (m, 2H), 7.71-7.76 (m, 2H), 7.81-7.85 (m, 2H), 7.92 (s, 1H), 8,61 (m, 1H), 8.74 (m, 1H), 8.7S (dd, 1H), 8.89 (s, 1H), 9.62 (br, NH). 1H NMR(acetone-d6) δ 1.25 (d, 6H), 4.18 (m, 1H), 7.38 (m, 1H), 7.59-7.64 (m, 2H), 7.71-7.76 (m, 2H), 7.81-7.85 (m, 2H), 7.92 (s, 1H), 8.61 (m, 1H), 8.74 (m, 1H), 8.7S (dd, 1H), 8.89 (s, 1H), 9.62 (br, NH) .
PRIMJER 3 EXAMPLE 3
N-izopropil-1-[3-(4-piridiniletmil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(4-pyridinylmethyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući 4-etinilpiridin (J.Org.Chem. 1996, 61, 6535) za fenilacetilen, naslovni spoj je dobiven kao krutina, After applying the procedure of Step 5 of EXAMPLE 1, but substituting 4-ethynylpyridine (J.Org.Chem. 1996, 61, 6535) for phenylacetylene, the title compound was obtained as a solid,
1H NMR (aceton-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.49 (m, 2H), 7.61 (m, 1H), 7.71-7.78 (m, 2H), 7.81 (m, 1H), 7.92 (s, 1H), 8.62 (m, 2H), 8,73 (m, 1H), 8.78 (dd, 1H), 8.87 (s, 1H), 9.62 (br, NH). 1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.49 (m, 2H), 7.61 (m, 1H), 7.71-7.78 (m, 2H), 7.81 (m, 1H ), 7.92 (s, 1H), 8.62 (m, 2H), 8.73 (m, 1H), 8.78 (dd, 1H), 8.87 (s, 1H), 9.62 (br, NH).
PRIMJER 4 EXAMPLE 4
N-izopropil-1-[3-(1-oksido-4-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(1-oxido-4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
U otopinu N-izopropil-1-[3-(4-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamida iz PRIMJERA 3 u metilen kloridu (36mL/mmol) i metanolu (3mL/mmol) je dodan magnezij monopcroksiftalat heksahidrat (MMPP, 3.6 eq) i smjesa je miješana na sobnoj temperaturi preko noći. Daljnja količina MMPP (2 eq) je dodana i miješanje je nastavljeno tijekom 24 sati. Rezultirajuća smjesa je filtrirana kroz sloj celita, filtrat je razrijeđen metilen kloridom i ispran vodenim natrij bikarbonatom u vodi. Nakon sušenja, organska faza je otparena i sirovi produkt je pročišćen kromatografijom na silika gelu, eluiran sa 10% metanol u metilen kloridu, da se dobije naslovni spoja kao krutina. In a solution of N-isopropyl-1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 3 in methylene chloride (36mL/mmol) and magnesium monoproxyphthalate hexahydrate (MMPP, 3.6 eq) was added to methanol (3mL/mmol) and the mixture was stirred at room temperature overnight. A further amount of MMPP (2 eq) was added and stirring was continued for 24 hours. The resulting mixture was filtered through a pad of celite, the filtrate was diluted with methylene chloride and washed with aqueous sodium bicarbonate in water. After drying, the organic phase was evaporated and the crude product was purified by silica gel chromatography, eluting with 10% methanol in methylene chloride, to give the title compound as a solid.
1H NMR (CDCl3) δ 1.28 (d, 6H), 4.28 (m, 1H), 7.35 (d, 2H), 7.46 (m, 2H), 7.58 (m, 2H), 7.67 (m, 1H), 8.14 (d, 2H), 8.69 (m, 1H), 8.81 (dd, 1H), 8.99 (s, 1H), 9.62 (br, NH). 1H NMR (CDCl3) δ 1.28 (d, 6H), 4.28 (m, 1H), 7.35 (d, 2H), 7.46 (m, 2H), 7.58 (m, 2H), 7.67 (m, 1H), 8.14 ( d, 2H), 8.69 (m, 1H), 8.81 (dd, 1H), 8.99 (s, 1H), 9.62 (br, NH).
PRIMJER 5 EXAMPLE 5
N-izopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksarnid N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxarnide
Korak 1: N-izopropil-1-r3-ftrimetilsiliIetininfenil1-1,4-dihidro[1,8]naftmdin-4-on-3-karboksamid. Step 1: N-isopropyl-1-[3-trimethylsilyl-ethyninphenyl]-1,4-dihydro[1,8]naphthmidine-4-one-3-carboxamide.
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući trimetilsililacetilen za fenilacetilen, N-izopropil-1-[3-(trimetilsiIiletiniI)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid produkt je dobiven i korišten u sljedećem koraku bez daljnjeg pročišćavanja. After applying the procedure from Step 5 of EXAMPLE 1, but substituting trimethylsilylacetylene for phenylacetylene, N-isopropyl-1-[3-(trimethylsilylethylene)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide product was obtained and used in the next step without further purification.
Korak 2: N-izopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 2: N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Sirovi produkt iz Koraka 1 je otopljen u metanolu (12mL/mmol) i dodana je 1N vodeni natrij hidroksid (3 eq), formirajući suspenziju. Suspenzijska smjesa je miješana na sobnoj temperaturi 2 sata, te je metanol otparen. Rezultirajuća vodena suspenzija je razrijeđena vodom, te je produkt ekstrahiran etil acetatom. Sirovi produkt je kromatografiran na silika gelu, eluiran sa 10% etera u metilen kloridu, da se dobije N-izopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid spoj kao krutina. The crude product from Step 1 was dissolved in methanol (12mL/mmol) and 1N aqueous sodium hydroxide (3 eq) was added, forming a suspension. The suspension mixture was stirred at room temperature for 2 hours, and the methanol was evaporated. The resulting aqueous suspension was diluted with water, and the product was extracted with ethyl acetate. The crude product was chromatographed on silica gel, eluting with 10% ether in methylene chloride, to give N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxamide compound as a solid.
1H NMR (aceton-d6) 1.24 (d, 6H), 3.81 (s, 1H), 4.17 (m, 1H), 7.59 (m, 1H), 7.64-7.71 (m, 3H), 7.81 (s, 1H), 8.72 (m, 1H), 8.76 (dd, 1H), 8.84 (s, 1H), 9,61 (br, NH). 1H NMR (acetone-d6) 1.24 (d, 6H), 3.81 (s, 1H), 4.17 (m, 1H), 7.59 (m, 1H), 7.64-7.71 (m, 3H), 7.81 (s, 1H) , 8.72 (m, 1H), 8.76 (dd, 1H), 8.84 (s, 1H), 9.61 (br, NH).
PRIMJER 6 EXAMPLE 6
N-ciklopropil-1-(3-etimlfem'l)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-cyclopropyl-1-(3-ethylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: N-ciklopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 1: N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka iz Koraka 4 PRIMJERA 1, ali mijenjajući ciklopropilamin za izopropilamin, N-ciklopropil-1-(3-bromofenil)-1,4-dihidro[1,8]nafliridin-4-on-3-karboksamid je dobiven kao prhka bijela krutina. After applying the procedure from Step 4 of EXAMPLE 1, but substituting cyclopropylamine for isopropylamine, N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]nafliridin-4-one-3-carboxamide was obtained as a powder white solid.
1H NMR (aceton-d6) δ 0.59 (m, 2H), 0.80 (m, 2h), 2.96 (m, 1H), 7.59-7.68 (m, 2H), 7.72 (dd, 1H), 7.82 (dd, 1H), 7.97 (s, 1H), 8.72-8.81 (m, 2H), 8.89 (s, 1H),9.70(br, NH). 1H NMR (acetone-d6) δ 0.59 (m, 2H), 0.80 (m, 2h), 2.96 (m, 1H), 7.59-7.68 (m, 2H), 7.72 (dd, 1H), 7.82 (dd, 1H ), 7.97 (s, 1H), 8.72-8.81 (m, 2H), 8.89 (s, 1H), 9.70 (br, NH).
Korak 2 i 3: N-ciklopropil-1-(3-etinilfenil)-1,4-dihidron.81naftiridin-4-on-3-karboksamid Step 2 and 3: N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydron.81-naphthyridin-4-one-3-carboxamide
Nakon postupaka iz Koraka 1 i 2 PRIMJERA. 5, ali mijenjajući produkt iz Koraka 1 za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, N-ciklopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid spoj je dobiven kao krutina. After the procedures from Steps 1 and 2 of the EXAMPLE. 5, but substituting the product from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, N-cyclopropyl-1-(3- ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDCl3) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, 1H), 3.18 (s, 1H), 7.42 (d, 1H), 7.47 (m, 1H), 7.52-7.58 (m, 2H), 7.65 (d, 1H), 8.70 (m, 1H), 8.80 (dd, 1H), 8.98 (s, 1H), 9,74 (br, NH). 1H NMR (CDCl3) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, 1H), 3.18 (s, 1H), 7.42 (d, 1H), 7.47 (m, 1H), 7.52- 7.58 (m, 2H), 7.65 (d, 1H), 8.70 (m, 1H), 8.80 (dd, 1H), 8.98 (s, 1H), 9.74 (br, NH).
PRIMJER 7 EXAMPLE 7
N-izopropil-1-[3-(3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući N-izopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksainidiz PRIMJERA 5 za fenilacetrlen i 3-bromopiridin za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamidJ naslovni spoj je dobiven kao svijetlo smeđa krutina. After applying the procedure from Step 5 of EXAMPLE 1, but substituting N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxanidise of EXAMPLE 5 for phenylacetylene and 3-bromopyridine for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide The title compound was obtained as a light brown solid.
1H NMR (aceton-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.43 (m, 1H), 7.61 (m, 1H), 7.70-7.75 (m, 2H), 7.80 (d, 1H), 7.90 (s, 1H), 7.94 (d, 1H), 8.58 (m, 1H), 8.74-8.79 (m, 3H), 8.88 (s, 1H), 9.62 (br, NH). 1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.43 (m, 1H), 7.61 (m, 1H), 7.70-7.75 (m, 2H), 7.80 (d, 1H) ), 7.90 (s, 1H), 7.94 (d, 1H), 8.58 (m, 1H), 8.74-8.79 (m, 3H), 8.88 (s, 1H), 9.62 (br, NH).
PRIMJER 8 EXAMPLE 8
N-izopropil-1-[3(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka PRJMJERA 4, ali mijenjajući N-izopropil-1-[3-(3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridm-4-on-3-karboksamidiz PRIMJERA 7 za N-izopropil-1-[3-(4-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, naslovni spoj je dobiven kao krutina. After applying the procedure of EXAMPLE 4, but substituting N-isopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridm-4-one-3-carboxamidase of EXAMPLE 7 for N-isopropyl -1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
1HNMR(CDCl3)δ 1.28(d,6H),4.28(mf lH),7.26(m, 1H),7.36(d; IH), 7.45-7.49 (m, 2H), 7.57-7.62 (m, 2H), 7.69 (d, 1H), 8.16 (d, 1H), 8.31 (s, 1H), 8.69 (m, 1H), 8.81 (dd, 1H), 8.99 (s, 1H), 9.63 (br, NH). 1HNMR(CDCl3)δ 1.28(d, 6H), 4.28(mf 1H), 7.26(m, 1H), 7.36(d; 1H), 7.45-7.49 (m, 2H), 7.57-7.62 (m, 2H), 7.69 (d, 1H), 8.16 (d, 1H), 8.31 (s, 1H), 8.69 (m, 1H), 8.81 (dd, 1H), 8.99 (s, 1H), 9.63 (br, NH).
PRIMJER 9 EXAMPLE 9
N-ciklopropil-1 -[3-(3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamld N-cyclopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući N-ciklopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid iz PRIMJERA 6 za fenilacetilen i 3-bromopiridin za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, naslovni spoj je dobiven kao krutina. After applying the procedure from Step 5 of EXAMPLE 1, but substituting N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6 for phenylacetylene and 3- bromopyridine for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
1H NMR (CDCl3) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, 1H), 7.28 (m, 1H), 7.43-7.48 (m, 2H), 7.57 (t, 1H), 7.62 (s, 1H), 7.70 (d, 1H), 7.79 (d, 1H), 8,55 (m, 1H), 8.70 (m, 1H), 8.75 (s, 1H), 8.79 (dd, 1H), 9.01 (s, 1H), 9.74 (br, NH). 1H NMR (CDCl3) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, 1H), 7.28 (m, 1H), 7.43-7.48 (m, 2H), 7.57 (t, 1H), 7.62 (s, 1H), 7.70 (d, 1H), 7.79 (d, 1H), 8.55 (m, 1H), 8.70 (m, 1H), 8.75 (s, 1H), 8.79 (dd, 1H) , 9.01 (s, 1H), 9.74 (br, NH).
PRIMJER 10 EXAMPLE 10
N-izopropil-1-[3-(3-Mdroksi-3-metilbut-1-inil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(3-Mhydroxy-3-methylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući 2-metil-3-butin-2-ol za fenilacetilen, naslovni spoj je dobiven kao bijela krutina. Following the procedure of Step 5 of EXAMPLE 1, but substituting 2-methyl-3-butyn-2-ol for phenylacetylene, the title compound was obtained as a white solid.
1HNMR (aceton-d6) δ 1.24 (d, 6H), 1.53 (s, 6H), 4.17 (m, 1H), 4.52 (s, 1H, OH), 7.58-7.65 (m, 4H), 7.68 (s, 1H), 8.72 (m, 1H), 8.77 (dd, 1H), 8.84 (s, 1H), 9.62 (br, NH). 1HNMR (acetone-d6) δ 1.24 (d, 6H), 1.53 (s, 6H), 4.17 (m, 1H), 4.52 (s, 1H, OH), 7.58-7.65 (m, 4H), 7.68 (s, 1H), 8.72 (m, 1H), 8.77 (dd, 1H), 8.84 (s, 1H), 9.62 (br, NH).
PRIMJER 11 EXAMPLE 11
N-ciklopropil-1-[3-(3-hidroksi-3-metilbut-1-inil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-cyclopropyl-1-[3-(3-hydroxy-3-methylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka PRIMJERA 10, ali mijenjajući N-ciklopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamidiz PRIMJERA 6 za N-izopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, naslovni spoj je dobiven kao bijela krutina. After applying the procedure of EXAMPLE 10, but substituting N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamidase of EXAMPLE 6 for N-isopropyl-1-(3 -ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a white solid.
1H NMR (aceton-d6) δ 0.57 (m, 2H), 0.78 (m, 2H), l .53 (s, 6H), 2.93 (m, 1H), 4.53 (s, 1H, OH), 7.58-7.65 (m, 4H), 7.67 (s, 1H), 8.72 (m, 1H), 8.76 (dd, 1H), 8.85 (s, 1H), 9,69 (br, NH). 1H NMR (acetone-d6) δ 0.57 (m, 2H), 0.78 (m, 2H), 1.53 (s, 6H), 2.93 (m, 1H), 4.53 (s, 1H, OH), 7.58-7.65 (m, 4H), 7.67 (s, 1H), 8.72 (m, 1H), 8.76 (dd, 1H), 8.85 (s, 1H), 9.69 (br, NH).
PRIMJER 12 EXAMPLE 12
N-izopropil-1-[3-(1-hidroksiciklopentil)etiniIfenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(1-hydroxycyclopentyl)ethynylphenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući 1-etinilciklopentanot za fenilacetilen, naslovni spoj je dobiven kao bijela krutina. Following the procedure of Step 5 of EXAMPLE 1, but substituting 1-ethynylcyclopentanoate for phenylacetylene, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 1.28(d,6H), 1.76-1.80 (m, 2H), 1.84-1.88 (m, 3H), 1.98-2.06 (m, 4H), 4.27 (m, 1H), 7,36 (d, 1H), 7,44-7.50 (m, 3H), 7,56 (d, 1H), 8.68 (m, 1H), 8.79 (dd, 1H), 8.97 (s, 1H), 9.63 (br, NH). 1H NMR (CDCl3) δ 1.28(d,6H), 1.76-1.80 (m, 2H), 1.84-1.88 (m, 3H), 1.98-2.06 (m, 4H), 4.27 (m, 1H), 7.36 (d, 1H), 7.44-7.50 (m, 3H), 7.56 (d, 1H), 8.68 (m, 1H), 8.79 (dd, 1H), 8.97 (s, 1H), 9.63 (br , NH).
PRIMJER 13 EXAMPLE 13
N-izopropiM-[3-(1-hidroksiciklopropil)etinilfenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-[3-(1-hydroxycyclopropyl)ethynylphenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: 1-etinilciklopropanol. Step 1: 1-ethynylcyclopropanol.
1-etinilciklopropanol je pripravljen Nakon primjene postupka opisanog uJ. Org.Chem. 1976,41, 1237 od [(1-etoksiciklopropil)oksi]trimetilsilana i etinil magnezij bromida, te dobiven kao tekućina. 1-ethynylcyclopropanol was prepared after applying the procedure described in J. Org.Chem. 1976,41, 1237 from [(1-ethoxycyclopropyl)oxy]trimethylsilane and ethynyl magnesium bromide, and obtained as a liquid.
Korak 2: N-izopropil-1-[3-(1-hidroksiciklopropilktinilfenil]-1,4-dihidron.81naftiridin-4-on-3-karboksamid. Step 2: N-isopropyl-1-[3-(1-hydroxycyclopropylctynylphenyl]-1,4-dihydron.81-naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući produkt iz Koraka 1 za fenilacetilen, N-izopropil-1-[3-(1-hidroksiciklopropil)etinilfenil]-1,4-dihidro[1,8]nafliridin-4-on-3-karboksamid spoj je dobiven kao krutina. After applying the procedure from Step 5 of EXAMPLE 1, but substituting the product from Step 1 for phenylacetylene, N-isopropyl-1-[3-(1-hydroxycyclopropyl)ethynylphenyl]-1,4-dihydro[1,8]nafliridin-4-one The -3-carboxamide compound was obtained as a solid.
1H NMR CCDCl3) δ 1.09 (m, 2H), 1.17(m,2H), 1.28 (d, 6H), 2.57(s, 1H, OH), 4.28 (m, 1H), 7.35 (d, 1H), 7.44-7.50 (m, 3H), 7.54 (d, 1H), 8.68 (m, 1H), 8.79 (dd, 1H), 8.96 (s, 1H), 9.63 (br, NH). 1H NMR CCDCl3) δ 1.09 (m, 2H), 1.17(m, 2H), 1.28 (d, 6H), 2.57(s, 1H, OH), 4.28 (m, 1H), 7.35 (d, 1H), 7.44 -7.50 (m, 3H), 7.54 (d, 1H), 8.68 (m, 1H), 8.79 (dd, 1H), 8.96 (s, 1H), 9.63 (br, NH).
PRIMJER 14 EXAMPLE 14
N-izopropil-1-{3-[4,4,4-trifluoro-3-hidroksi-3-(trifluorometil)but-1-inil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-1-ynyl]phenyl}-1,4-dihydro[1,8]naphthyridine-4- on-3-carboxamide
Korak 1:1,1,1-trifIuoro-2-( trifluorometil)-4-(trimetilsilil)but-3-in-2-ol. Step 1: 1,1,1-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol.
U otopinu trimetilsililacetilena (4mL) u THF (30mL) na -78°C je dodano 2.5M n-butillitija u heksanima (14mL) i rezultirajuća smjesa je miješana tijekom l sata. Višak heksafluoroacetona je propuhan u hladnu smjesu, tejemiješanje nastavljeno tijekom 4 sata, Nakon zagrijavanja do sobne temperature, smjesa je gažena zasićenom vodenom otpinom amonij klorida i odijeljena između etera i vode. Organska faza je osušena i otparena da se dobije 1,1,1-Mfluoro-2-(trifiuorometil)-4-(trimetilsilil)but-3-in-2-ol kao tekućina. To a solution of trimethylsilylacetylene (4mL) in THF (30mL) at -78°C was added 2.5M n-butyllithium in hexanes (14mL) and the resulting mixture was stirred for 1 hour. Excess hexafluoroacetone was blown into the cold mixture, and stirring was continued for 4 hours. After warming to room temperature, the mixture was triturated with saturated aqueous ammonium chloride solution and partitioned between ether and water. The organic phase was dried and evaporated to give 1,1,1-Mfluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol as a liquid.
Korak 2:N-izopropil-1-{3-[4,4,4-trifluoro-3-hidroksi-3-(trifluorometil)but-1-inil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 2: N-isopropyl-1-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-1-ynyl]phenyl}-1,4-dihydro[1,8]naphthyridine -4-one-3-carboxamide.
U otopinu 1,1,1-trifluoro-2-(trifluorometil)-4-(trimetilsilil)but-3-in-2-ola iz Koraka 1 (6.8mmol) u 10mL THF je dodan 1M tetrabutilamonij fluorida (8.5mL) i rezultirajuća smjesa je refluksirana tijekom 30 minuta da se ukloni TMS zaštitna grupa. Postupak iz Koraka 5 PRIMJERA 1 je zatim primijenjenj ali mijenjajući ovu otopinu za fenilacetilen, da se dobije N-izopropil-1-{3-[4,4,4-trifluoro-3-hidroksi-3-(trifluorometil)but-1-inil]fenil}-1,4-dinidro[1,8]naftiridin-4-on-3-karboksamid spoj kao krutina. To a solution of 1,1,1-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol from Step 1 (6.8 mmol) in 10 mL of THF was added 1 M tetrabutylammonium fluoride (8.5 mL) and the resulting mixture was refluxed for 30 min to remove the TMS protecting group. The procedure of Step 5 of EXAMPLE 1 was then applied, but substituting this solution for phenylacetylene, to give N-isopropyl-1-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-1- inyl]phenyl}-1,4-dinidro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
1H NMR (aceton-d6) δ 1.24 (d, 6H), 4.17 (m, 1H), 7.60 (m, 1H), 7.72-7.79 (m, 2H), 7.83 (d, 1H), 7.90 (s, 1H), 8.14 (s, 1H, OH), 8.72 (m, 1H), 8.77 (dd, 1H), 8.85(s, 1H),9.62(br, NH). 1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.17 (m, 1H), 7.60 (m, 1H), 7.72-7.79 (m, 2H), 7.83 (d, 1H), 7.90 (s, 1H ), 8.14 (s, 1H, OH), 8.72 (m, 1H), 8.77 (dd, 1H), 8.85 (s, 1H), 9.62 (br, NH).
PRIMJER 15 EXAMPLE 15
N-izopropil-1-[3-(3-hidroksi-3-feniIbut-1-inil)fenil]-1,4-dihidro[1,8]naftiridm-4-on-3-karboksamid N-isopropyl-1-[3-(3-hydroxy-3-phenylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridim-4-one-3-carboxamide
Smjesa N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamida iz Koraka 4 PRIMJERA 1, 2-fenil-3-butin-2-ola (2 eq), trietilamina (1.66 eq), bis(difenilfosfino)ferocen]dikloropaladija(n) (0.05 eq), i bakar (I) jodida (5mg/mmol) u DMF (20mL/mmol) je zagrijavana na 85°C tijekom 18 sati. Nakon hlađenja do sobne temperature, rezultirajuća smjesa je gažena zasićenom vodenom otopinom amonij klorida i odijeljena između etil acetata i vode. Sirovi produkt organske faze je kromatografiran na silika gelu, eluiran sa 20% etera u metilen kloridu. Pročišćeni produkt je miješan u eteru na sobnoj temperaturi tijekom 3 sata, te filtriran, da se dobije naslovni spoja kao bijela krutina. A mixture of N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 4 of EXAMPLE 1, 2-phenyl-3-butyn-2-ol ( 2 eq), triethylamine (1.66 eq), bis(diphenylphosphino)ferrocene]dichloropalladium(n) (0.05 eq), and copper(I) iodide (5mg/mmol) in DMF (20mL/mmol) was heated at 85°C for 18 hours. After cooling to room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The crude product of the organic phase was chromatographed on silica gel, eluted with 20% ether in methylene chloride. The purified product was stirred in ether at room temperature for 3 hours and filtered to give the title compound as a white solid.
1H NMR(aceton-d6) δ 1.24 (d, 6H), 1.79 (s, 3H), 4.18 (m, 1H), 5.22 (s, 1H, OH), 7.26 (t, 1H), 7.35 (t, 2H)S 7.59 (m, 1H), 7.66 (m, 3H), 7.73 (d, 2H), 7.76 (s, 1H), 8.72 (m, 1H), 8.77 (dd, 1H), 8.84 (s, 1H), 9.62 (br, NH). 1H NMR(acetone-d6) δ 1.24 (d, 6H), 1.79 (s, 3H), 4.18 (m, 1H), 5.22 (s, 1H, OH), 7.26 (t, 1H), 7.35 (t, 2H )S 7.59 (m, 1H), 7.66 (m, 3H), 7.73 (d, 2H), 7.76 (s, 1H), 8.72 (m, 1H), 8.77 (dd, 1H), 8.84 (s, 1H) , 9.62 (no, NH).
PRIMJER 16 EXAMPLE 16
N-ciklopropil-1-[3-(1-oksido-3-piridiniletmil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-cyclopropyl-1-[3-(1-oxido-3-pyridinylyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: 3-etinilpiridin N-oksid. Step 1: 3-ethynylpyridine N-oxide.
U otopinu 3-etinilpiridina u metilen kloridu (5mL/mmol) na sobnoj temperaturi je dodana m-kloroperoksibenzojeva kiselina (m-CPBA, 70% čistoća, 1.2 eq) i rezultirajuća smjesa je miješana tijekom 2 sata. Daljnja količina m-CPBA je dodana (0,25 eq) i miješanje je nastavljeno tijekom l sata. Kalcij hidroksid je dodan (2 eq) i nakon 15 minuta smjesa je filtrirana kroz celit i filtrat otparen. Ostatak krutine je miješan u eteru tijekom 3 sata i filtriran, da se dobije 3-etinilpiridin N-oksid spoj kao bijela krutina. To a solution of 3-ethynylpyridine in methylene chloride (5mL/mmol) at room temperature was added m-chloroperoxybenzoic acid (m-CPBA, 70% purity, 1.2 eq) and the resulting mixture was stirred for 2 hours. A further amount of m-CPBA was added (0.25 eq) and stirring was continued for 1 hour. Calcium hydroxide (2 eq) was added and after 15 minutes the mixture was filtered through celite and the filtrate was evaporated. The remaining solid was stirred in ether for 3 hours and filtered to give the 3-ethynylpyridine N-oxide compound as a white solid.
Korak 2: N-ciklooropil-1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 2: N-cyclooropropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka PRIMJERA 15, ali mijenjajući N-ciklopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid iz Koraka 1 PRIMJERA 6 za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]nafliridin-4-on-3-karboksamid, i 3-etinilpiridin N-oksid iz Koraka 1 za 2-fenil-3-butin-2-ol, N-ciklopropil-1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid spoj je dobiven kao bijela krutina, After applying the procedure of EXAMPLE 15, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 of EXAMPLE 6 for N-isopropyl-1 -(3-bromophenyl)-1,4-dihydro[1,8]nafliridin-4-one-3-carboxamide, and 3-ethynylpyridine N-oxide from Step 1 for 2-phenyl-3-butyn-2-ol, The N-cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid,
1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 2.96 (m, l H), 7.26 (m, 1H), 7.37 (d, 1H), 7.45-7.48 (m, 2H), 7.58-7.62 (m, 2H), 7.69 (d, 1H), 8.16 (d, 1H), 8.31 (s, 1H), 8.69 (m, 1H), 8.79 (dd, 1H), 8.99 (s, 1H), 9.73 (br, NH). 1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 2.96 (m, 1H), 7.26 (m, 1H), 7.37 (d, 1H), 7.45-7.48 (m, 2H) , 7.58-7.62 (m, 2H), 7.69 (d, 1H), 8.16 (d, 1H), 8.31 (s, 1H), 8.69 (m, 1H), 8.79 (dd, 1H), 8.99 (s, 1H ), 9.73 (no, NH).
PRIMJER 17 EXAMPLE 17
N-izopropil-1-[3-(3-amino-3-etilpent-1-inil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(3-amino-3-ethylpent-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz PRIMJERA 15, ali mijenjajući 1,1-dietilpropargilamin za 2-fenil-3-butin-2-ol, naslovni spoj je dobiven kao krutina. Following the procedure of EXAMPLE 15, but substituting 2-phenyl-3-butyn-2-ol for 1,1-diethylpropargylamine, the title compound was obtained as a solid.
1HNMR (CDCl3) δ 1.05 (t, 6H), 1.28 (d, 6H), 1.57 (m, 2H), 1.69 (m, 2H), 4.27 (m, 1H), 7.33 (d, 1H), 7.44-7.49 (m, 3H), 7.53 (d, 1H), 8.69 (m, 1H), 8.79 (dd, 1H), 8.97 (s, 1H), 9.63 (br, NH). (NH2 nije zapažen). 1HNMR (CDCl3) δ 1.05 (t, 6H), 1.28 (d, 6H), 1.57 (m, 2H), 1.69 (m, 2H), 4.27 (m, 1H), 7.33 (d, 1H), 7.44-7.49 (m, 3H), 7.53 (d, 1H), 8.69 (m, 1H), 8.79 (dd, 1H), 8.97 (s, 1H), 9.63 (br, NH). (NH2 was not observed).
PRIMJER 18 EXAMPLE 18
N-ciklopropil-1-[3-(3-amino-3-etilpent-1-inil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-cyclopropyl-1-[3-(3-amino-3-ethylpent-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz PRIMJERA 17, ali mijenjajući N-ciklopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamidiz Koraka 1 PRIMJERA 6 zaN-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, naslovni spoj je dobiven kao krutina. After applying the procedure of EXAMPLE 17, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamidiz of Step 1 of EXAMPLE 6 for N-isopropyl-1- (3-Bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 1.05 (t, 6H), 1.57 (m, 2H), 1.70 (m, 2H), 2.96 (m, 1H), 7.33 (d, 1H), 7.44-7.49 (m, 3H), 7.54 (d, 1H), 8.69 (m, 1H), 8.77 (dd, 1H), 8.97 (s, 1H), 9.75 (br, NH). (NH2 nije zapažen). 1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 1.05 (t, 6H), 1.57 (m, 2H), 1.70 (m, 2H), 2.96 (m, 1H), 7.33 ( d, 1H), 7.44-7.49 (m, 3H), 7.54 (d, 1H), 8.69 (m, 1H), 8.77 (dd, 1H), 8.97 (s, 1H), 9.75 (br, NH). (NH2 was not observed).
PRIMJER 19 EXAMPLE 19
N-izopropil-1-[3-(3-kvinoHniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(3-quinophenylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka iz PRIMJERA 15, ali mijenjajući N-izopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid iz Koraka 2 PRIMJERA 5 za 2-fenil-3-butin-2-ol, i 3-bromokvinolin za N-izopropil-1-(3-bromofenil)-1-dihidro[1,8]naftiridin-4-on-3-karboksamid, naslovni spoj je dobiven kao krutina. After applying the procedure of EXAMPLE 15, but substituting N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2 of EXAMPLE 5 for 2-phenyl- 3-butyn-2-ol, and 3-bromoquinoline for N-isopropyl-1-(3-bromophenyl)-1-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
1H NMR (CDCl3) δ 1.32(d,6H),4.32(m, 1H), 7.48-7.51 (m, 2H), 7.58-7.65 (m, 2H), 7.71 (s, 1H), 7.73-7.80 (m, 2H), 7.83 (d, 1H), 8,12 (d, 1H), 8.35 (s, 1H), 8.75 (m, 1H), 8.85 (dd, 1H), 9.02 (s, 1H), 9.06 (s, 1H), 9.65 (br, NH). 1H NMR (CDCl3) δ 1.32(d, 6H), 4.32(m, 1H), 7.48-7.51 (m, 2H), 7.58-7.65 (m, 2H), 7.71 (s, 1H), 7.73-7.80 (m , 2H), 7.83 (d, 1H), 8.12 (d, 1H), 8.35 (s, 1H), 8.75 (m, 1H), 8.85 (dd, 1H), 9.02 (s, 1H), 9.06 ( s, 1H), 9.65 (br, NH).
PRIMJER 20 EXAMPLE 20
N-izopropil-1-[3-(1-oksido-3-kvinoliniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(1-oxido-3-quinolinylethenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka PRIMJERA 19, ali mijenjajući 3-bromokvinolin N-oksid za 3-bromokvinolin, naslovni spoj je dobiven kao krutina. Following the procedure of EXAMPLE 19, but substituting 3-bromoquinoline N-oxide for 3-bromoquinoline, the title compound was obtained as a solid.
1H NMR (CDCl3) δ 1.33 (d, 6H), 4.32 (m, 1H), 7.49-7.53 (m, 2H), 7.63 (t, 1H), 7.68-7.73 (m, 2H), 7.75-7.83 (m, 2H), 7.88-7.92 (m, 2H), 8,63 (s, 1H), 8.73-8.78 (m, 2H), 8.86 (dd, 1H), 9.05 (s, 1H), 9.67 (br, NH). 1H NMR (CDCl3) δ 1.33 (d, 6H), 4.32 (m, 1H), 7.49-7.53 (m, 2H), 7.63 (t, 1H), 7.68-7.73 (m, 2H), 7.75-7.83 (m , 2H), 7.88-7.92 (m, 2H), 8.63 (s, 1H), 8.73-8.78 (m, 2H), 8.86 (dd, 1H), 9.05 (s, 1H), 9.67 (br, NH ).
PRIMJER 21 EXAMPLE 21
N-izopropil-1-[3-(ciklopropiletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamiđ N-isopropyl-1-[3-(cyclopropylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka PRIMJERA 15, ali mijenjajući ciklopropilacetilen (Tetrahedron letters 2000, 41,4007) za 2-fenil-3-butin-2-ol, naslovni spoj je dobiven kao siva krutina. Following the procedure of EXAMPLE 15, but substituting cyclopropylacetylene (Tetrahedron letters 2000, 41,4007) for 2-phenyl-3-butyn-2-ol, the title compound was obtained as a gray solid.
1H NMR (CDCl3) 5 0.83 (m, 2H), 0.90 (m, 2H), 1.31 (d, 6H), 1.48 (m, 1H), 4.31 (m, 1H), 7.33 (m, 1H), 7.45-7.51 (m, 3H), 7.55 (d, 1H), 8.72 (m, 1H), 8.83 (dd, 1H), 9.01 (s, 1H), 9.68 (br, NH). 1H NMR (CDCl3) δ 0.83 (m, 2H), 0.90 (m, 2H), 1.31 (d, 6H), 1.48 (m, 1H), 4.31 (m, 1H), 7.33 (m, 1H), 7.45- 7.51 (m, 3H), 7.55 (d, 1H), 8.72 (m, 1H), 8.83 (dd, 1H), 9.01 (s, 1H), 9.68 (br, NH).
PRIMJER 22 EXAMPLE 22
N-izopropil-1-[3-(6-amino-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-[3-(6-amino-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Nakon primjene postupka PRIMJERA 19, ali mijenjajući 5-bromo-2-aminopiridin za 3-bromokvinolin, naslovni spoj je dobiven kao krutina. Following the procedure of EXAMPLE 19, but substituting 5-bromo-2-aminopyridine for 3-bromoquinoline, the title compound was obtained as a solid.
1H NMR (CDCl3) δ 1.33 (d, 6H), 4.31 (m, 1H), 4.71 (br, NH2), 6.49 (d, 1H), 7.40 (m, 1H), 7.48 (m, 1H), 7.54-7.60 (m, 3H), 7.68 (d, 1H), 8.28 (s, 1H), 8.72 (m, 1H), 8.83 (dd, 1H), 9.04 (s, 1H), 9.67 (br, NH). 1H NMR (CDCl3) δ 1.33 (d, 6H), 4.31 (m, 1H), 4.71 (br, NH2), 6.49 (d, 1H), 7.40 (m, 1H), 7.48 (m, 1H), 7.54- 7.60 (m, 3H), 7.68 (d, 1H), 8.28 (s, 1H), 8.72 (m, 1H), 8.83 (dd, 1H), 9.04 (s, 1H), 9.67 (br, NH).
PRIMJER 23 EXAMPLE 23
N-izopropil-1-{3-[5-(1-hidroksi-1-metiletil)-1-oksido-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide
Korak 1: 3-bromo-5-(1-hidroksi-1-metiletil)piridin. Step 1: 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine.
U otopinu etil 5-bromonikotinata (1.02g, 4.4rαmol) u dietil eteru (15mL) na -30°C je dodana 3M otopina metil magnezij bromida u eteru (4mL, 12mmol), Rezultirajuća smjesa je refluksirana 2 sata, zatim ohlađena i gašena suviškom 0.5M vodenog monobaznog natrij fosfata, te odijeljena između etera i vode. Produkt organske faze je kromatografiran na silika gelu, eluiran sa 2:1:2 smjesom etera, pentana i amonijem-zasićenog metilen klorida, da se dobije spoj 3-bromo-5-(1-hidroksi-1-metiletil)piridin kao žuto ulje. A 3M solution of methyl magnesium bromide in ether (4mL, 12mmol) was added to a solution of ethyl 5-bromonicotinate (1.02g, 4.4rαmol) in diethyl ether (15mL) at -30°C. The resulting mixture was refluxed for 2 hours, then cooled and quenched. with an excess of 0.5M aqueous monobasic sodium phosphate, and separated between ether and water. The organic phase product was chromatographed on silica gel, eluting with a 2:1:2 mixture of ether, pentane and ammonium-saturated methylene chloride, to give the compound 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine as a yellow oil .
Korak 2: 3-bromo-5-(1-hidroksi-1-metiletil)piridin-N-oksid. Step 2: 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide.
U otopinu 3-bromo-5-(1-hidroksi-1-metiletil)piridina iz Koraka 1 (3.1 mmol) u klorofonnu (10mL) je dodana m-kloroperoksibenzojeva kiselina 70% (1.5 eq) i rezultirajuća smjesa je miješana na sobnoj temperaturi tijekom 18 sati. Dodan je suvišak kalcij hidroksida i nakon miješanja od 5 minuta smjesa je filtrirana kroz celit i filtrat je otparen. Sirovi materijal je kromatografiran na silika gelu, eluiran sa 10% etanola u metilen kloridu (zasićen amonijem) da se dobije 3-bromo-5-(1-hidroksi-1-metiletil)piridin-N-oksid spoj kao krutina. To a solution of 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine from Step 1 (3.1 mmol) in chlorophonic (10 mL) was added m-chloroperoxybenzoic acid 70% (1.5 eq) and the resulting mixture was stirred at room temperature during 18 hours. An excess of calcium hydroxide was added and after stirring for 5 minutes the mixture was filtered through celite and the filtrate was evaporated. The crude material was chromatographed on silica gel, eluting with 10% ethanol in methylene chloride (saturated with ammonium) to give the 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide compound as a solid.
Korak 3: N-izopropil-1-{3-[5-(1-hidroksi-1-metiletin-1-oksido-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 3: N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyn-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one -3-carboxamide.
Nakon primjene postupka PRIMJERA 15, ali mijenjajući N-izopropil-1-(3-etinilfenil)-1,4-diMdro[1,8]naftiridin-4-on-3-karboksamid iz PRIMJERA 5 za 2-fenil-3-butin-2-ol, i 3-bromo-5-(1-hidroksi-1-metiletil)piridin-N-oksid iz Koraka 2 za N-izopropil-1(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, dobiven je spoj N-izopropil-1-{3-[5-(1-hidroksi-1-metiletil)-1-oksido-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid kao krutina. After applying the procedure of EXAMPLE 15, but changing N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 5 for 2-phenyl-3-butyne -2-ol, and 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide from Step 2 for N-isopropyl-1(3-bromophenyl)-1,4-dihydro[1,8 ]naphthyridin-4-one-3-carboxamide, the compound N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4 -dihydro[1,8]naphthyridin-4-one-3-carboxamide as a solid.
1H NMR CDCl3) δ 1.32(d,6H), 1.64 (s, 6H),2.22 (br, 1H, OH), 4.30 (m, 1H), 7.45-7.52 (m, 2H), 7.60 (t, 1H), 7.66 (s, 1H), 7.72 (d, 1H), 7.98 (s, 1H), 8.70 (br, 2H), 8.73 (m, 1H), 8.84 (dd, 1H), 9.03 (s, 1H), 9.68 (br, NH). 1H NMR CDCl3) δ 1.32(d, 6H), 1.64 (s, 6H), 2.22 (br, 1H, OH), 4.30 (m, 1H), 7.45-7.52 (m, 2H), 7.60 (t, 1H) , 7.66 (s, 1H), 7.72 (d, 1H), 7.98 (s, 1H), 8.70 (br, 2H), 8.73 (m, 1H), 8.84 (dd, 1H), 9.03 (s, 1H), 9.68 (no, NH).
PRIMJER 24 EXAMPLE 24
N-izopropil-1-{3-[6-(1-hidroksi-1-metiletil)-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: 5-bromo-2-(1-hidroksi-1-meriletinpiridin. Step 1: 5-bromo-2-(1-hydroxy-1-merylethynepyridine).
U suspenziju 2,5-dibromopiridina u toluenu (12mL/mmol) ohlađenu do -78°C je dodan n-butillitij 2.5M u heksanima (1.05eq) i rezultirajuća smjesa je miješana na hladnom tijekom 2.5 sata. Aceton (2eq) je dodan i miješanje je nastavljeno tijekom l .5h. Nakon gašenja zasićenom vodenom otopinom amonij klorida, smjesa je zagrijana do sobne temperature i odijeljena između etil acetata i vode. Produkt organske faze je kromatografiran na silika gelu, eluiran sa 20% etil acetata u heksanu, da se dobije spoj 5-bromo-2-(1-hidroksi-1-metiletil) piridin kao sirup. To a suspension of 2,5-dibromopyridine in toluene (12mL/mmol) cooled to -78°C was added n-butyllithium 2.5M in hexanes (1.05eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (2eq) was added and stirring was continued for 1.5 h. After quenching with saturated aqueous ammonium chloride, the mixture was warmed to room temperature and partitioned between ethyl acetate and water. The organic phase product was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane, to give the compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine as a syrup.
Korak 2: 5-bromo-2-(1-metil-1-{[2-(trimetilsilil)etoksi]metoksi}etil)piridin. Step 2: 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine.
U otopinu 5-bromo-2-(1-hidroksi-1-metiletil) piridina iz Koraka 1 (14mmol) u metilen kloridu (50mL) na 0°C je dodan N,N-diizopropiletilamin (37.3mmol) i 2-(trimetilsilil)etoksimetil klorid (15.3mmol). Rezultirajuća smjesa je miješana na sobnoj temperaturi tijekom 18 sati, zatim refluksirana tijekom 24 sata. Nakon hlađenja do sobne temperature, smjesa je gažena zasićenom vodenom otopinom amonij klorida i odijeljena između metilen klorida i vode. Sirovi produkt organske faze je kromatografiran na silika gelu, eluiran sa 6% etil acetata u heksanu, da se dobije spoj 5-bromo-2-(1-metil-1-{[2-(trimetiIsilil)etoksi]metoksi}etil)piridin, N,N-diisopropylethylamine (37.3 mmol) and 2-(trimethylsilyl) were added to a solution of 5-bromo-2-(1-hydroxy-1-methylethyl) pyridine from Step 1 (14 mmol) in methylene chloride (50 mL) at 0°C. )ethoxymethyl chloride (15.3 mmol). The resulting mixture was stirred at room temperature for 18 hours, then refluxed for 24 hours. After cooling to room temperature, the mixture was quenched with saturated aqueous ammonium chloride and partitioned between methylene chloride and water. The crude product of the organic phase was chromatographed on silica gel, eluting with 6% ethyl acetate in hexane, to give the compound 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine ,
Korak 3: 2-(1-metil-1-{[2-(trimetilsilil)eoksi]metoksi}etil)-5-[(trimetilsilil)etinil]piridin. Step 3: 2-(1-methyl-1-{[2-(trimethylsilyl)eoxy]methoxy}ethyl)-5-[(trimethylsilyl)ethynyl]pyridine.
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući produkt iz Koraka 2 za N-izopropil-1-(3-bromofeni])-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid i trimetilsililacetilen za fenilacetilen, dobiven je spoj 2-(1-metil-1-{[2-(trimetilsilil)etoksi]metoksi}etil)-5-[(trimetilsilil)etinil]piridin. After applying the procedure from Step 5 of EXAMPLE 1, but substituting the product from Step 2 for N-isopropyl-1-(3-bromophenyl])-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for phenylacetylene, the compound 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-5-[(trimethylsilyl)ethynyl]pyridine was obtained.
Korak 4: 5-etinil-2-(1-metil-1-{[2-(trimetilsilil)etoksi]metoksi}etil)piridin. Step 4: 5-ethynyl-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine.
Nakon primjene postupka iz Koraka 2 PRIMJERA 5, ali mijenjajući produkt iz Koraka 3 za N-izopropil-1-[3-(trimetilsililetinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, dobiven je spoj 5-etinil-2-(1-metil-1-{[2-(trimetilsilil)etoksi]metoksi}etil)piridin. After applying the procedure from Step 2 of EXAMPLE 5, but substituting the product from Step 3 for N-isopropyl-1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide , the compound 5-ethynyl-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine was obtained.
Korak 5: N-izopropil-1-(3-{[6-(1-metil-1-{{2-trimetilsilil)etoksi]metoksi}etil)piridin-3-il]etinil}fenil)-1,4-dihidro[1,8]naftiridin-4-on-3 -karboksamid. Step 5: N-isopropyl-1-(3-{[6-(1-methyl-1-{{2-trimethylsilyl)ethoxy]methoxy}ethyl)pyridin-3-yl]ethynyl}phenyl)-1,4- dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući produkt iz Koraka 4 za fenilacetilen, dobiven je spoj N-izopropil-1-(3-{[6-(1-metil-1-{{2-trimetilsilil)etoksi]metoksi}etil)piridin-3-il]etinil}fenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. After applying the procedure from Step 5 of EXAMPLE 1, but changing the product from Step 4 for phenylacetylene, the compound N-isopropyl-1-(3-{[6-(1-methyl-1-{{2-trimethylsilyl)ethoxy]methoxy) was obtained }ethyl)pyridin-3-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Korak 6: N-izopropil-1-(3-[6-(1-hidroksi-1-metiletil)-3-piridiniletinl}fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksainid. Step 6: N-isopropyl-1-(3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethyl}phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxainide.
U otopinu N-izopropil-1-(3-{[6-(1-metil-1-{{2-trimetilsilil)etoksi]metoksi}etil)piridin-3-il]etinil}fenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid produkta iz Koraka 5 u metilen kloridu (32mL/mmol) na 0°C je dodana trifluorooctena kiselina (3.2mL/mmol). Rezultirajuća smjesa je miješana na 0°C 2 sata a zatim na sobnoj temperaturi 2 sata. Smjesa je neutralizirana polagano, zasićenim vodenim natrij bikarbonatom i odijeljena između metilen klorida i vode. Sirovi materijal organske faze je kromatografiran na silika gelu eluiran sa 40% etera u metilen kloridu i pročišćeni produkt je miješan u eteru na sobnoj temperaturi 2 sata i filtriran da se dobije N-izopropiI-1-{3-[6-(1-hidroksi-1-metiletil)-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid spoj kao krutina. In solution N-isopropyl-1-(3-{[6-(1-methyl-1-{{2-trimethylsilyl)ethoxy]methoxy}ethyl)pyridin-3-yl]ethynyl}phenyl)-1,4-dihydro Trifluoroacetic acid (3.2 mL/mmol) was added to the [1,8]naphthyridin-4-one-3-carboxamide product from Step 5 in methylene chloride (32 mL/mmol) at 0°C. The resulting mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours. The mixture was neutralized slowly with saturated aqueous sodium bicarbonate and partitioned between methylene chloride and water. The crude material of the organic phase was chromatographed on silica gel eluted with 40% ether in methylene chloride and the purified product was stirred in ether at room temperature for 2 hours and filtered to give N-isopropyl-1-{3-[6-(1-hydroxy -1-methylethyl)-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
1H NMR (aceton-d6) δ 1.24 (d, 6H), 1.50 (s, 6H), 4.18 (m, 1H), 4.57 (s, 1H, OH), 7.61 (m, 1H), 7.69-7.74 (m, 3H), 7.78 (m, 1H), 7.88 (s, 1H), 7.93 (dd, 1H), 8.68 (s, 1H), 8.74 (m, 1H), 8.78 (dd, 1H), 8.88 (s, 1H), 9.63 (br, NH). 1H NMR (acetone-d6) δ 1.24 (d, 6H), 1.50 (s, 6H), 4.18 (m, 1H), 4.57 (s, 1H, OH), 7.61 (m, 1H), 7.69-7.74 (m , 3H), 7.78 (m, 1H), 7.88 (s, 1H), 7.93 (dd, 1H), 8.68 (s, 1H), 8.74 (m, 1H), 8.78 (dd, 1H), 8.88 (s, 1H), 9.63 (br, NH).
PRIMJER 25 EXAMPLE 25
N-izopropil-1-{3-[6-(1-hidroksi-1-metiletil)-1-oksido-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide
Nakon primjene postupka iz Koraka 2 PRIMJERA 23, ali mijenjajući N-izopropil-1-{3-[6-(1-hidroksi-1-metiletil)-3-piridiniletinil]feni]}-1,4-dihidro[1,8]nafliridin-4-on-3-karboksamid iz PRIMJERA 24 za 3-bromo-5-(1-hidroksi-1-metiletil)piridm, naslovni spoj je dobiven kao krutina. After applying the procedure from Step 2 of EXAMPLE 23, but changing N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethynyl]phenyl]}-1,4-dihydro[1,8 ]nafliridin-4-one-3-carboxamide from EXAMPLE 24 for 3-bromo-5-(1-hydroxy-1-methylethyl)pyridm, the title compound was obtained as a solid.
1H NMR (aceton-d6) δ 1.25 (d, 6H), 1.60 (s, 6H), 4.18 (m, 1H), 7.24 (s, 1H, OH), 7.60-7.63 (m, 3H), 7.72-7.78 (m, 2H), 7.82 (d, 1H), 7.91 (s, 1H), 8.46 (s, 1H), 8.74 (m, 1H), 8.78 (dd, 1H), 8.87 (s, 1H), 9.62 (br, NH). 1H NMR (acetone-d6) δ 1.25 (d, 6H), 1.60 (s, 6H), 4.18 (m, 1H), 7.24 (s, 1H, OH), 7.60-7.63 (m, 3H), 7.72-7.78 (m, 2H), 7.82 (d, 1H), 7.91 (s, 1H), 8.46 (s, 1H), 8.74 (m, 1H), 8.78 (dd, 1H), 8.87 (s, 1H), 9.62 ( no, NH).
PRIMJER 26 EXAMPLE 26
N-izopropil-1-{3-[4-(1-hidroksi-1-metiletil)-2-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: meti] 2-bromoizonikotinat. Step 1: methy]2-bromoisonicotinate.
U otopinu 2-bromoizonikotinske kiseline (Chem. Pharm. Buli. 1990, 38, 2446) (2.0g) u tctrahidrofuranu (100mL) je dodan suvišak eteralnog diazometana i rezultirajuća smjesa je miješana na sobnoj temperaturi tijekom l sata. Smjesa je otparena i produkt kromatografiran na silika gelu, eluiran sa 1:3 smjesom etila acetat i heksana, da se dobije metil 2-bromoizonikotinat ester kao bezbojna tekućina. To a solution of 2-bromoisonicotinic acid (Chem. Pharm. Buli. 1990, 38, 2446) (2.0g) in tetrahydrofuran (100mL) was added an excess of ethereal diazomethane and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the product chromatographed on silica gel, eluted with a 1:3 mixture of ethyl acetate and hexane, to give methyl 2-bromoisonicotinate ester as a colorless liquid.
Korak 2: 2-bromo-4-(1-hidroksi-1-metiletinpiridin. Step 2: 2-bromo-4-(1-hydroxy-1-methylethynpyridine).
Nakon primjene postupka iz Koraka 1 PRIMJERA 23, ali mijenjajući metil 2-bromoizonikotinat iz Koraka 1 za etil 5-bromonikotinat, dobiven je spoj 2-bromo-4-(1-hidroksi-1-metiletil)piridin kao bijela krutina. After applying the procedure from Step 1 of EXAMPLE 23, but changing methyl 2-bromoisonicotinate from Step 1 for ethyl 5-bromonicotinate, the compound 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine was obtained as a white solid.
Korak 3: N-izopropil-1-{3-[4-(1-hidroksi-1-metiletil)-2-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 3: N-isopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxamide.
Nakon primjene postupka PRIMJERA 19, ali mijenjajući 2-bromo-4-(1-hidroksi-1-rnetiletil)piridin iz Koraka 2 za 3-bromokvinolin, dobiven je spoj N-izopropil-1-{3-[4-(1-hidroksi-1-metiletiI)-2-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid kao žuta pjena. After applying the procedure of EXAMPLE 19, but substituting 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine from Step 2 for 3-bromoquinoline, the compound N-isopropyl-1-{3-[4-(1- hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a yellow foam.
1H NMR (aceton-d6) δ l .27 (d, 6H), 1.55 (s, 6H), 4.20 (m, 1 H), 4.42 (s, 1H, OH), 7.52 (m, 1H), 7.63 (m, 1H), 7.72-7.79 (m, 3H), 7.84 (d, 1H), 7.95 (s, 1H), 8.55 (d, 1H), 8.77 (m, 1H), 8.80 (dd, 1H), 8.92 (s, 1H), 9.65 (br, NH). 1H NMR (acetone-d6) δ l .27 (d, 6H), 1.55 (s, 6H), 4.20 (m, 1H), 4.42 (s, 1H, OH), 7.52 (m, 1H), 7.63 ( m, 1H), 7.72-7.79 (m, 3H), 7.84 (d, 1H), 7.95 (s, 1H), 8.55 (d, 1H), 8.77 (m, 1H), 8.80 (dd, 1H), 8.92 (s, 1H), 9.65 (br, NH).
PRIMJER 27 EXAMPLE 27
N-izopropil-1-{3-[5-(1-hidroksi-1-metiletil)-2-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: 2-bromo-5-(1-hidroksi-1-metiletil)piridin. Step 1: 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine.
Otopina 2,5-dibromopiridina u dietil eteru (5mL/mmol) je ohlađena do -78°C, i polagano je dodavan n-butillitij 2,5M u heksanima(1.05 eq). Nakon 2 sata na hladnom, dodan je aceton (1.3 eq) i miješanje je nastavljeno tijekom l sata. Rezultirajuća smjesa je gašena zasićenom vodenom otopinom amonij klorida, zagrijana do sobne temperature, i odijeljena između etera i vode. Surovi produkt organske faze je trituriran sa 1:1 eter-heksan i filtriran da se dobije spoj 2-bromo-5-(1-hidroksi-1-metiletil)piridin kao krutina. A solution of 2,5-dibromopyridine in diethyl ether (5mL/mmol) was cooled to -78°C, and n-butyllithium 2.5M in hexanes (1.05 eq) was slowly added. After 2 hours in the cold, acetone (1.3 eq) was added and stirring was continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature, and partitioned between ether and water. The crude product of the organic phase was triturated with 1:1 ether-hexane and filtered to give the compound 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine as a solid.
Korak 2: 5-(1-hidroksi-1-metiletil)-2-[(trimetilsilil)etinil]piridin. Step 2: 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine.
Nakon primjene postupka iz PRIMJERA 15, ali mijenjajući produkt 2-bromo-5-(1-hidroksi-1-metiletil)piridin iz Koraka 1 za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid i trimetilsililacetilen za 2-fenil-3-butin-2-ol, dobiven je spoj 5-(1-hidroksi-1-metiletil)-2-[(trimetilsilil)etinil]piridin. After applying the procedure from EXAMPLE 15, but changing the product 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1, 8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for 2-phenyl-3-butyn-2-ol, the compound 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine was obtained .
Korak 3: 2-etinil-5-(1-hidroksi-1-metiletil)piridin. Step 3: 2-ethynyl-5-(1-hydroxy-1-methylethyl)pyridine.
Nakon primjene postupka iz Koraka 2 PRIMJERA 5, ali mijenjajući produkt 5-(1-hidroksi-1-metiletil)-2-[(trimetilsilil)etinil]piridin iz Koraka 2 za N-izopropil-1-[3-(trimetilsililetinil)fenil]-1,4-dihidro[1,8]naftiridLn-4-on-3-karboksamid, dobiven je spoj 2-etinil-5-(1-hidroksi-1-metiletil)piridin. After applying the procedure from Step 2 of EXAMPLE 5, but changing the product 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine from Step 2 for N-isopropyl-1-[3-(trimethylsilylethynyl)phenyl ]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the compound 2-ethynyl-5-(1-hydroxy-1-methylethyl)pyridine was obtained.
Korak 4: N-izopropil-1-{3-[5-(1-hidroksi-1-metiletil)-2-piridiniletinil]fenil}-1,4-dihidro[1.8]naftiridin-4-on-3-karboksamid. Step 4: N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1.8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka iz PRIMJERA 15 ali mijenjajući produkt 2-etinil-5-(1-hidroksi-1-rnetiletil)piridin iz Koraka 3 za 2-fentt-3-butin-2-ol, dobiven je spoj N-izopropil-1-{3-[5-(1-hidroksi-1-metileti1)-2-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. After applying the procedure from EXAMPLE 15 but changing the product 2-ethynyl-5-(1-hydroxy-1-methylethyl)pyridine from Step 3 for 2-phent-3-butyn-2-ol, the compound N-isopropyl-1- {3-[5-(1-Hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
1H NMR (CDCl3) δ l .32 (d, 6H), 1.66 (s, 6H), 2.08 (s, l H, OH), 4.31 (m, 1H), 7.46-7.55 (m, 3H), 7.61 (t, 1H), 7.71 (s, 1H), 7.78 (d, 1H), 7.86 (dd, 1H), 8.73 (m, 1H), 8.77 (m, 1H), 8.83 (dd, 1H), 9.04 (s, 1H), 9,67 (br, NH). 1H NMR (CDCl3) δ l .32 (d, 6H), 1.66 (s, 6H), 2.08 (s, l H, OH), 4.31 (m, 1H), 7.46-7.55 (m, 3H), 7.61 ( t, 1H), 7.71 (s, 1H), 7.78 (d, 1H), 7.86 (dd, 1H), 8.73 (m, 1H), 8.77 (m, 1H), 8.83 (dd, 1H), 9.04 (s , 1H), 9.67 (br, NH).
PRIMJER 28 EXAMPLE 28
N-izopropil-1-{3-[6-(1-hidroksi-1-metiletil)-2-piridiniletmil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-2-pyridinylmethyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: 2-bromo-6-(1-hidroksi-1-meti]etil)piridin. Step 1: 2-bromo-6-(1-hydroxy-1-methyl]ethyl)pyridine.
Nakon primjene postupka iz Koraka 1 PRIMJERA 27, ali mijenjajući 2,6-dibromopiridin za 2,5-dibromopiridin, dobiven je spoj 2-bromo-6-(1-hidroksi-1-metiletil)piridin kao krutina. After applying the procedure from Step 1 of EXAMPLE 27, but replacing 2,6-dibromopyridine with 2,5-dibromopyridine, the compound 2-bromo-6-(1-hydroxy-1-methylethyl)pyridine was obtained as a solid.
Korak 2 :N-izopropil-1-{3-[6-(1-hidroksi-1-metiletil)-2-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 2: N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxamide.
Nakon primjene postupka iz PRIMJERA 19, ali mijenjajući produkt 2-bromo-6-(1-hidroksi-1-metiletil)piridin iz Koraka 1 za 3-bromokvinolin, dobivanje spoj N-izopropil-1-{3-[6-(1-hidroksi-1-metiletil)-2-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. After applying the procedure from EXAMPLE 19, but changing the product 2-bromo-6-(1-hydroxy-1-methylethyl)pyridine from Step 1 for 3-bromoquinoline, obtaining the compound N-isopropyl-1-{3-[6-(1 -hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
1H NMR (CDCl3) δ l .31 (d, 6H), l .58 (s, 6H), 4.32 (m, 1H), 4.83 (s, 1H, OH), 7.38 (d, 1H), 7.43-7.52 (m, 3H), 7.60 (t, 1H), 7.70-7.75 (m, 2H), 7.79 (d, 1H), 8.74 (m, 1H), 8.84 (dd, 1H), 9.03 (s, 1H), 9.66 (br, NH). 1H NMR (CDCl3) δ l .31 (d, 6H), l .58 (s, 6H), 4.32 (m, 1H), 4.83 (s, 1H, OH), 7.38 (d, 1H), 7.43-7.52 (m, 3H), 7.60 (t, 1H), 7.70-7.75 (m, 2H), 7.79 (d, 1H), 8.74 (m, 1H), 8.84 (dd, 1H), 9.03 (s, 1H), 9.66 (no, NH).
PRIMJER 29 EXAMPLE 29
N-ciklopropil-1-{3-[6-(1-hidroksi-1-metiletil)-1-oksido-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide
Korak 1: 5-bromo-2-(1-hidroksi-1-metiletinpiridinN-oksid. Step 1: 5-bromo-2-(1-hydroxy-1-methylethynpyridineN-oxide).
Nakon primjene postupka iz Koraka 2 PRIMJERA 23, ali mijenjajući 5-bromo-2-(1-hidroksi-1-metiletil)piridin iz Koraka 1 PRIMJERA 24 za 3-bromo-5-(1-hidroksi-1-metiletil)piridm, dobiven je spoj 5-bromo-2-(1-hidroksi-1-metiletil)piridin N-oksid. After applying the procedure from Step 2 of EXAMPLE 23, but substituting 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 of EXAMPLE 24 for 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine, the compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine N-oxide was obtained.
Korak 2: N-ciklopropil-1-{3-[6-(1-hidroksi-1-metiletil)-1-oksido-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 2: N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridine-4- on-3-carboxamide.
Nakon primjene postupka PRIMJERA 15, ali mijenjajući N-ciklopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid iz PRIMJERA 6 za 2-fenil-3-butin-2-ol i 5-bromo-2-(1-hidroksi-1-metiletil)piridin-N-oksid iz Koraka 1 za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, dobiven je spoj N-ciklopropil-1-{3-[6-(1-hidroksi-1-metiletil)-1-oksido-3-piridiniletinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksaimd krutina. After applying the procedure of EXAMPLE 15, but changing N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6 for 2-phenyl-3-butyne -2-ol and 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine-N-oxide from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8 ]naphthyridin-4-one-3-carboxamide, the compound N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4 -dihydro[1,8]naphthyridin-4-one-3-carboxamide solid.
1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), l .66 (s, 6H), 2.96 (m, 1H), 7.34 (d, 1H), 7.43-7.50 (m, 4H), 7.58-7.62 (m, 2H), 7.69 (d, 1H), 8.33 (s, 1H, OH), 8.69 (m, 1H), 8.79 (dd, 1H), 8.99 (s, 1H), 9.73 (br, NH). 1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 1.66 (s, 6H), 2.96 (m, 1H), 7.34 (d, 1H), 7.43-7.50 (m, 4H ), 7.58-7.62 (m, 2H), 7.69 (d, 1H), 8.33 (s, 1H, OH), 8.69 (m, 1H), 8.79 (dd, 1H), 8.99 (s, 1H), 9.73 ( no, NH).
PRIMJER 30 EXAMPLE 30
N-izopropil-1-{3-[(4-piridin-3-ilfenil)etinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: 3-(4-bromofenil)piridin. Step 1: 3-(4-bromophenyl)pyridine.
Smjesa piridin-3-boronske kiseline, 1,3-propandiol cikličkog estera, 4-bromojodobenzena (1.1 eq), [1,1'-bis (difenilfosfino)ferocen]dik]oropaladija(II) (0.05 eq) i 2M vodenog natrij karbonata (5 eq) u N,N-dimetilformamidu (2mL/mmol) je miješana na 85°C tijekom 4 sati. Nakon gašenja zasićenom vodenom otopinom amonij klorida, smjesa je odijeljena između etil acetata i vode, te je sirovi produkt organske faze kromatografiran na silika gelu, eluiran sa l :9 smjesom etila acetat i heksana da se dobije 3-(4-bromofenil)piridin spoj kao krutina. A mixture of pyridine-3-boronic acid, 1,3-propanediol cyclic ester, 4-bromoiodobenzene (1.1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dic]oropalladium(II) (0.05 eq) and 2M aqueous sodium of carbonate (5 eq) in N,N-dimethylformamide (2mL/mmol) was stirred at 85°C for 4 hours. After quenching with a saturated aqueous solution of ammonium chloride, the mixture was partitioned between ethyl acetate and water, and the crude product of the organic phase was chromatographed on silica gel, eluted with a 1:9 mixture of ethyl acetate and hexane to obtain the 3-(4-bromophenyl)pyridine compound as a solid.
Korak 2: N-izopropil-1-{3-[(4-piridin-3-ilfenil)etinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 2: N-isopropyl-1-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka PRIMJERA 19, ali mijenjajući produkt iz Koraka 1 za 3-bromokvinolin, dobiven je spoj N-izopropil-1-{3-[(4-piridin-3-ilfenil)etinil]fenil}-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. After applying the procedure of EXAMPLE 19, but changing the product from Step 1 for 3-bromoquinoline, the compound N-isopropyl-1-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-1,4-dihydro[ 1,8]naphthyridin-4-one-3-carboxamide.
1HNMR (CDCl3) δ 1.28 (d, 6H), 4.28 (m, 1H), 7,38 (m, 1H), 7.42 (d, 1H), 7.48 (m, 1H), 7.53-7.64 (m, 6H), 7.70 (d, 1H), 7.88 (d, 1H), 8.60 (m, 1H), 8.71 (m, 1H), 8.82 (dd, 1H), 8.86 (s, 1H), 9.02 (s, 1H), 9.63 (br, NH). 1HNMR (CDCl3) δ 1.28 (d, 6H), 4.28 (m, 1H), 7.38 (m, 1H), 7.42 (d, 1H), 7.48 (m, 1H), 7.53-7.64 (m, 6H) , 7.70 (d, 1H), 7.88 (d, 1H), 8.60 (m, 1H), 8.71 (m, 1H), 8.82 (dd, 1H), 8.86 (s, 1H), 9.02 (s, 1H), 9.63 (no, NH).
PRIMJER 31 EXAMPLE 31
N-izopropil-1-(3-{[5-(1-hidroksi-1-metiletil)tien-2-il]etinil}fenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-(3-{[5-(1-hydroxy-1-methylethyl)thien-2-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide
Korak 1: 2-bromo-5-(1-hidroksi-1-metiletil)tiofen. Step 1: 2-bromo-5-(1-hydroxy-1-methylethyl)thiophene.
U otopinu 2-acetil-5-bromotiofena u THF (2.5mL/mmol) na -30°C je dodan 1.4M metilmagnezij bromidu3:l toluen-THF(1.5 eq) i rezultirajuća smjesa je zagrijavana do-10°C i miješana tijekom 1.5 sati. Nakon gašenja zasićenom vodenom otopinom amonij klorida, smjesa je odijeljena između etera i vode. Organska frakcija je osušena i otparena, i sirovi materijal je kromatografiran na silika gelu, eluiran sa t :4 smjesom etera i heksanaa, da se dobije 2-bromo-5-(1-hidroksi-1-metiletil)tiofen spoja. To a solution of 2-acetyl-5-bromothiophene in THF (2.5mL/mmol) at -30°C was added 1.4M methylmagnesium bromide 3:1 toluene-THF (1.5 eq) and the resulting mixture was warmed to -10°C and stirred for 1.5 hours. After quenching with saturated aqueous ammonium chloride, the mixture was partitioned between ether and water. The organic fraction was dried and evaporated, and the crude material was chromatographed on silica gel, eluting with a t:4 mixture of ether and hexane, to give the 2-bromo-5-(1-hydroxy-1-methylethyl)thiophene compound.
Korak 2: 2-(1-hidroksi-1-metiletil)-5-trimetilsililetinil tiofen. Step 2: 2-(1-hydroxy-1-methylethyl)-5-trimethylsilylethynyl thiophene.
Nakon primjene postupka iz PRIMJERA 15, ali mijenjajući produkt iz Koraka 1 zaN-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid i trimetilsililacetilen za 2-fenil-3-butin-2-ol, 2-(1-hidroksi-1-metiletil)-5-trimetilsililetinil tiofen spoj je dobiven. After applying the procedure from EXAMPLE 15, but changing the product from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for 2-phenyl -3-butyn-2-ol, 2-(1-hydroxy-1-methylethyl)-5-trimethylsilylethynyl thiophene compound was obtained.
Korak 3: 2-etinil-5-(1-hidroksi-1-metiletil)tiofen. Step 3: 2-ethynyl-5-(1-hydroxy-1-methylethyl)thiophene.
Nakon primjene postupka iz Koraka 2 PRIMJERA 5, ali mijenjajući produkt iz Koraka 2 za N-izopropil-1-[3-(trimetilsililetinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, 2-etinil-5-(1-hidroksi-1-metiletil)tiofen spoj je dobiven. After applying the procedure from Step 2 of EXAMPLE 5, but substituting the product from Step 2 for N-isopropyl-1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide , 2-ethynyl-5-(1-hydroxy-1-methylethyl)thiophene compound was obtained.
Korak 4 : N-izopropil-1-(3-{[5-(1-hidroksi-1-metiletil)tien-2-il]etinil}fenin-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 4: N-isopropyl-1-(3-{[5-(1-hydroxy-1-methylethyl)thien-2-yl]ethynyl}phenin-1,4-dihydro[1,8]naphthyridin-4-one -3-carboxamide.
Nakon primjene postupka PRIMJERA 15, ali mijenjajući 2-etinil-5-(1-hidroksi-1-metiletil)tiofen produkt iz Koraka 3 za 2-fenil-3-butin-2-ol, N-izopropil-1-(3-{[5-(1-hidroksi-1-metiletil)tien-2-il]etinil}fenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid spoj je dobiven kao krutina. After applying the procedure of EXAMPLE 15, but changing the 2-ethynyl-5-(1-hydroxy-1-methylethyl)thiophene product from Step 3 for 2-phenyl-3-butyn-2-ol, N-isopropyl-1-(3- The {[5-(1-hydroxy-1-methylethyl)thien-2-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR CDCl3) δ 1.31 (d, 6H), 1.70 (s, 6H), 2.42 (s, 1H, OH), 4.31 (m, 1H), 6.87 (d, 1H), 7.16 (d, 1H), 7.42 (d, 1H), 7.48 (m, 1H), 7.59 (t, 1H), 7.63 (s, 1H), 7.68 (d, 1H), 8.73 (m, 1H), 8.84 (dd, 1H), 9.02 (s, 1H), 9.68 (br, NH). 1H NMR CDCl3) δ 1.31 (d, 6H), 1.70 (s, 6H), 2.42 (s, 1H, OH), 4.31 (m, 1H), 6.87 (d, 1H), 7.16 (d, 1H), 7.42 (d, 1H), 7.48 (m, 1H), 7.59 (t, 1H), 7.63 (s, 1H), 7.68 (d, 1H), 8.73 (m, 1H), 8.84 (dd, 1H), 9.02 ( s, 1H), 9.68 (br, NH).
PRIMJER 32 EXAMPLE 32
N-izopropil-1-(3-{[2-(1-hidroksi-1-metiletil)-1,3-tiazol-5-il]ctinil}fenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid N-isopropyl-1-(3-{[2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl]ctynyl}phenyl)-1,4-dihydro[1,8]naphthyridine- 4-one-3-carboxamide
Korak 1: 2-(1-hidroksi-1-metiletil) tiazol. Step 1: 2-(1-hydroxy-1-methylethyl) thiazole.
U otopinu tiazola u eteru (1mL/mmol) na -78°C je dodan 2.2M n-butillitij u heksanima (1.1 eq) i rezultirajuća smjesa je miješana tijekom 30 minuta. Aceton (1.2 eq) je dodan i smjesa je miješana na-78°C daljnjih 30 minuta. Smjesa je gašena u hladnoj zasićenoj vodenoj otopini amonij klorida i zagrijana do sobne temperature, zatim odijeljena između etera i vode. Organska faza je osušena i otparena, da se dobije sirovi produkt kao narančasto-smeđe ulje, koje je korišteno kao takvo u sljedećem koraku. To a solution of thiazole in ether (1mL/mmol) at -78°C was added 2.2M n-butyllithium in hexanes (1.1 eq) and the resulting mixture was stirred for 30 minutes. Acetone (1.2 eq) was added and the mixture was stirred at -78°C for a further 30 minutes. The mixture was quenched in cold saturated aqueous ammonium chloride and warmed to room temperature, then partitioned between ether and water. The organic phase was dried and evaporated to give the crude product as an orange-brown oil, which was used as such in the next step.
Korak 2: 2-(1-metil-1-{[2-(trimetilsilil)etoksi]metoksi}etil)tiazol. Step 2: 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole.
Nakon primjene postupka iz Koraka 2 PRIMJERA 24, ali mijenjajući produkt iz Koraka 1 za 5-bromo-2-(1-hidroksi-1-metiletil) piridin, 2-(1-metil-1-{[2-(trimetilsilil)etoksi]metoksi}etil)tiazol spoj je dobiven kao ulje. After applying the procedure from Step 2 of EXAMPLE 24, but substituting the product from Step 1 for 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy The ]methoxy}ethyl)thiazole compound was obtained as an oil.
Korak 3: 5-bromo-2-(1-hidroksi-1-metiletiI)tiazol. Step 3: 5-bromo-2-(1-hydroxy-1-methylethyl)thiazole.
U otopinu 2-(1-metil-1-{[2-(trimetilsilil)etoksi]metoksi}etil)tiazol iz Koraka 2 u kloroformu (2mL/mmol) na sobnoj temperaturi je dodan bromin (2 molar eq) i rezultirajuća smjesa je miješana tijekom l sata. Krutina natrij bikarbonata (0.55 eq) je dodana i smjesa je miješana narednih 5 sati. Dodano je još natrij bikarbonata (0.55 eq) i miješanje je nastavljeno tijekom 18 sati. Nakon konačnog dodavanja natrij bikarbonata, (0.55 eq) smjesa je miješana tijekom 5 sati, razrijeđena kloroformom, te je organska faza isprana zasićenim vodenim natrij bikarbonatom, zatim vodom, osušena i otparena. Sirovi materijal je kromatografiran, eluiran sa 3:7 smjesom etila acetat i heksana, da se dobije željeni produkt. Bromine (2 molar eq) was added to a solution of 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole from Step 2 in chloroform (2mL/mmol) at room temperature and the resulting mixture was stirred for 1 hour. Solid sodium bicarbonate (0.55 eq) was added and the mixture was stirred for the next 5 hours. More sodium bicarbonate (0.55 eq) was added and stirring was continued for 18 hours. After the final addition of sodium bicarbonate, (0.55 eq) the mixture was stirred for 5 hours, diluted with chloroform, and the organic phase was washed with saturated aqueous sodium bicarbonate, then with water, dried and evaporated. The crude material was chromatographed, eluted with a 3:7 mixture of ethyl acetate and hexane, to give the desired product.
Korak 4: N-izopropil-1-(3-{[2-(1-hidroksi-1-metiletin-1,3-tiazol-5-il]etiniL}feniL)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 4: N-isopropyl-1-(3-{[2-(1-hydroxy-1-methylethyn-1,3-thiazol-5-yl]ethynyl}phenyl)-1,4-dihydro[1,8] naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka PRIMJERA 19, ali mijenjajući produkt iz Koraka 3 za 3-bromokvinolin, i dobiven je spoj N-izopropil-1-(3-{[2-(1-hidroksi-1-metiletil)-1,3-tiazol-5-il]etinil}fenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid kao krutina. After applying the procedure of EXAMPLE 19, but changing the product from Step 3 for 3-bromoquinoline, the compound N-isopropyl-1-(3-{[2-(1-hydroxy-1-methylethyl)-1,3-thiazol- 5-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a solid.
1H NMR CDCl3) δ 1.29(d,6H), 1.68 (s, 6H), 2.90 (s, 1H, OH), 4.28 (m, 1H), 7.42 (d, 1H), 7.46 (m, 1H), 7.54-7.60 (m, 2H), 7.66 (d, 1H), 7.82 (s, 1H), 8.70 (m, 1H), 8.80 (dd, 1H), 8.99 (s, 1H), 9.63 (br, NH). 1H NMR CDCl3) δ 1.29(d,6H), 1.68 (s, 6H), 2.90 (s, 1H, OH), 4.28 (m, 1H), 7.42 (d, 1H), 7.46 (m, 1H), 7.54 -7.60 (m, 2H), 7.66 (d, 1H), 7.82 (s, 1H), 8.70 (m, 1H), 8.80 (dd, 1H), 8.99 (s, 1H), 9.63 (br, NH).
PRIMJER 33 EXAMPLE 33
1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide
Korak 1: 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 1: 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka iz Koraka 4 PRIMJERA 1, ali mijenjajući 28% vodena amonij hidroksid za izopropilamin, dobiven je spoj 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid kao krutina. After applying the procedure from Step 4 of EXAMPLE 1, but substituting 28% aqueous ammonium hydroxide for isopropylamine, the compound 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide was obtained as solid.
Korak 2: 1-[3-(trimetilsililetinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 2: 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka iz Koraka 5 PRIMJERA 1, ali mijenjajući 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid iz Koraka 1 za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamidi trimetilsililacetilen za fenilacetilen, 1-[3-(trimetilsililetinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid produkt je dobiven kao krutina. After applying the procedure from Step 5 of EXAMPLE 1, but substituting 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 for N-isopropyl-1-(3 -bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamides trimethylsilylacetylene for phenylacetylene, 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridine- The 4-one-3-carboxamide product was obtained as a solid.
Korak 3: 1-(3-etinilfenin-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 3: 1-(3-ethynylphenine-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide).
U otopinu 1-[3-(trimetilsililetinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamida iz Koraka 2 u THF (30mL/mmol) na 0°C je dodan 1M tetrabutilamonij fluorida u THF (1.5 eq) i rezultirajuća smjesa je miješana na 0°C 30 minuta. Smjesa je odijeljena između metilen klorida i vode, te je organska faza osušena i otparena. Sirovi 1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid produkt je korišten kao takav u sljedećem koraku. 1M tetrabutylammonium was added to a solution of 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2 in THF (30mL/mmol) at 0°C fluoride in THF (1.5 eq) and the resulting mixture was stirred at 0°C for 30 min. The mixture was partitioned between methylene chloride and water, and the organic phase was dried and evaporated. The crude 1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide product was used as such in the next step.
Korak 4: 1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid. Step 4: 1-[3-(1-Oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.
Nakon primjene postupka PRIMJERA 19, ali mijenjajući 1-(3-etinilfenil)-1,4-dihidro[1,8]nafliridin-4-on-3-karboksamid iz Koraka 3 za N-izopropil-1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid i 3-bromopiridin N-oksid za 3-bromokvinolin, dobiven je 1-[3-(1-oksido-3-piridiniletmil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid kao bijela krutina. After applying the procedure of EXAMPLE 19, but substituting 1-(3-ethynylphenyl)-1,4-dihydro[1,8]nafliridin-4-one-3-carboxamide from Step 3 for N-isopropyl-1-(3-ethynylphenyl) -1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and 3-bromopyridine N-oxide for 3-bromoquinoline, 1-[3-(1-oxido-3-pyridinylmethyl)phenyl] -1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
1H NMR CDCl3) δ 5.84 (br, 1H,NH), 7.30 (m, 1H), 7.41 (d, 1H), 7.53 (m, 2H), 7.64 (t, 1H), 7.67 (s, 1H), 7.74 (d, 1H), 8.21 (d, 1H), 8.35 (s, 1H), 8.75 (m, 1H), 8.88 (dd, 1H), 9.05 (s, 1H), 9.52 (br, 1H, NH). 1H NMR CDCl3) δ 5.84 (br, 1H,NH), 7.30 (m, 1H), 7.41 (d, 1H), 7.53 (m, 2H), 7.64 (t, 1H), 7.67 (s, 1H), 7.74 (d, 1H), 8.21 (d, 1H), 8.35 (s, 1H), 8.75 (m, 1H), 8.88 (dd, 1H), 9.05 (s, 1H), 9.52 (br, 1H, NH).
PRIMJER 34 EXAMPLE 34
1-[3-(1-oksido-3-piridiniletiml)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilna kiselina 1-[3-(1-oxido-3-pyridinylethyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid
Korak 1: etil l-r3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilat. Step 1: Ethyl 1-[3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate.
Nakon postupaka iz Koraka 1 i 2 PRIMJERA 5, ali mijenjajući etil 1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilat iz Koraka 2 PRIMJERA 1 za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid kao početni materijal, etil 1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilat spoj je dobiven kao krutina. Following the procedures from Steps 1 and 2 of EXAMPLE 5, but substituting ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 of EXAMPLE 1 for N-isopropyl- 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as starting material, ethyl 1-(3-ethynylphenyl)-1,4-dihydro[1,8] the naphthyridin-4-one-3-carboxylate compound was obtained as a solid.
Korak 2: etil 1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilat. Step 2: Ethyl 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate.
Nakon primjene postupka iz PRIMJERA 15, ali mijenjajući etil 1-(3-etinilfenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilat iz Koraka 1 za 2-fenil-3-butin-2-ol i 3-bromopiridin N-oksid za N-izopropil-1-(3-bromofenil)-1,4-dihidro[1,8]naftiridin-4-on-3-karboksamid, etil 1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]nafliridin-4-on-3-karboksilat je dobiven kao krutina. After applying the procedure from EXAMPLE 15, but substituting ethyl 1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 1 for 2-phenyl-3-butyn-2 -ol and 3-bromopyridine N-oxide for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, ethyl 1-[3-(1 -oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]nafliridin-4-one-3-carboxylate was obtained as a solid.
Korak 3: 1-[3-(1-oksido-3-piridiniletininfenin-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilnu kiselinu. Step 3: 1-[3-(1-Oxido-3-pyridinylethyninephenine-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid).
Nakon primjene postupka iz Koraka 3 PRIMJERA 1, ali mijenjajući etil 1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilat ester iz Koraka 2 za etil 1-(3-bromofenil)-1,4-dihidro[1,8]nafttridin-4-on-3-karboksilat, 1-[3-(1-oksido-3-piridiniletinil)fenil]-1,4-dihidro[1,8]naftiridin-4-on-3-karboksilna kiselina je dobivene kao bijela krutina. After applying the procedure from Step 3 of EXAMPLE 1, but changing the ethyl 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate ester from of Step 2 for Ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthtridin-4-one-3-carboxylate, 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1 ,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid was obtained as a white solid.
1H NMR (DMSO-d6) δ 7.46 (t, 1H), 7.51 (d, 1H), 7.70 (t, 1H), 7.75 (m, 2H), 7.80 (d, 1H), 7.92 (s, 1H), 8.26 (d, 1H), 8.47 (s, 1H), 8.81 (dd, 1H), 8.89 (m, 1H), 8.97 (s, 1H). 1H NMR (DMSO-d6) δ 7.46 (t, 1H), 7.51 (d, 1H), 7.70 (t, 1H), 7.75 (m, 2H), 7.80 (d, 1H), 7.92 (s, 1H), 8.26 (d, 1H), 8.47 (s, 1H), 8.81 (dd, 1H), 8.89 (m, 1H), 8.97 (s, 1H).
Druge varijacije ili modifikacije, koje su očite stručnim osobama, su obuhvaćene obimom i sadržajem ovog izuma. Ovaj izum nije ničim ograničen, osim kako je navedeno u sljedećim zahtjevima. Other variations or modifications, which will be apparent to those skilled in the art, are included within the scope and spirit of this invention. This invention is not limited except as set forth in the following claims.
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